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Alpha-1 adrenergic receptor

The α1-adrenergic receptors (α1-ARs) are a subclass of G protein-coupled receptors (GPCRs) that bind endogenous catecholamines, such as norepinephrine and epinephrine, to mediate diverse physiological responses in the sympathetic nervous system.^[1] These receptors feature a characteristic seven-transmembrane domain structure, with a ligand-binding pocket in the hydrophobic core involving key residues like aspartate in transmembrane helix 3 and serines in helix 5. Recent cryo-EM structures have elucidated the agonist specificity and activation mechanisms of the α1A subtype.^[2]^[3] Upon activation, α1-ARs primarily couple to Gq/11 proteins, stimulating phospholipase C to produce inositol trisphosphate (IP3) and diacylglycerol (DAG), which elevate intracellular calcium levels and activate protein kinase C (PKC), though alternative pathways like Gi coupling or β-arrestin signaling can occur in specific contexts.^[1] There are three pharmacologically distinct subtypes—α1A, α1B, and α1D—each encoded by separate genes and exhibiting tissue-specific expression patterns.^[3] The α1A subtype predominates in the brain (e.g., hippocampus and cortex, comprising ~55% of cerebral α1-ARs), prostate, and vascular smooth muscle; α1B is abundant in the heart, liver, and certain brain regions like the thalamus and amygdala (~35%); while α1D is less prevalent overall (~10% in the brain) but significant in large arteries and the spinal cord.^[4] Subtype selectivity arises from differences in binding affinities for ligands, such as the α1A-preferring agonist A-61603 or antagonist 5-methylurapidil, guided historically by the Easson-Stedman hypothesis on catecholamine stereochemistry.^[3] In physiology, α1-ARs regulate critical processes including vasoconstriction and vascular smooth muscle contraction (via α1 subtypes, particularly α1D in large arteries), positive inotropy and cardioprotection in the heart (α1A and α1B), glucose metabolism and uptake (α1A), and smooth muscle tone in the urinary tract.^[1] In the central nervous system, they modulate neurotransmission by enhancing glutamate and GABA release in regions like the prefrontal cortex and hypothalamus, often through calcium channel modulation.^[4] Furthermore, α1-ARs influence synaptic plasticity, promoting long-term potentiation (LTP) in hippocampal and amygdalar circuits to support memory consolidation and fear learning, while also inducing long-term depression (LTD) in certain synapses.^[4] Pharmacologically, α1-AR agonists like phenylephrine are used to treat hypotension and shock by inducing vasoconstriction, whereas antagonists such as prazosin target hypertension, benign prostatic hyperplasia (BPH), and post-traumatic stress disorder symptoms through smooth muscle relaxation and reduced noradrenergic signaling.^[1] Dysregulation of α1-ARs contributes to conditions like heart failure (where α1A activation offers protection but α1B may promote maladaptive hypertrophy), Alzheimer's disease (with reduced α1A expression impairing cognition), and metabolic syndrome (via impaired glucose handling).^[1] Ongoing research explores subtype-selective ligands for enhanced therapeutic precision in these disorders.^[3]

Molecular Structure

Protein Architecture

The alpha-1 adrenergic receptor is a seven-transmembrane domain glycoprotein that belongs to the rhodopsin-like family (class A) of G protein-coupled receptors (GPCRs).^[5]^[6] As a typical GPCR, it features an extracellular N-terminal domain, seven α-helices spanning the plasma membrane to form a binding pocket, three intracellular loops, and an intracellular C-terminal tail. The N-terminus is located extracellularly and contains consensus sites for N-linked glycosylation, which contributes to receptor maturation and trafficking to the cell surface. The C-terminus extends into the cytoplasm and includes phosphorylation sites that regulate receptor desensitization and signaling.^[5]^[7] The seven α-helical transmembrane domains (TM1–TM7) form a characteristic bundle that creates the core architecture of the receptor, with the ligand-binding pocket situated within this transmembrane region. Insights from the crystal structure of the human α1B subtype, resolved at 2.9 Å resolution in 2022, reveal a 7TM bundle where TM1 is tilted outward due to crystal packing, and TM4 is elongated compared to α2-adrenergic receptors, resembling β-adrenergic receptors. The orthosteric binding site, located deep within the transmembrane bundle, accommodates catecholamines such as norepinephrine and epinephrine, as approximated from related GPCR structures like the β2-adrenergic receptor bound to epinephrine. Additionally, the structure identifies allosteric modulation sites in secondary pockets near TM2, TM3, and TM7, which influence ligand selectivity and binding affinity. For crystallization, the N-terminus (residues M1–N34) was truncated, and the C-terminus was replaced with a designed ankyrin repeat protein (DARPin) chaperone to stabilize helix 8.^[8] Post-translational modifications play crucial roles in the receptor's structural integrity and function. N-linked glycosylation occurs at four asparagine residues in the extracellular N-terminus, resulting in a core-glycosylated precursor form of approximately 70 kDa that matures to about 90 kDa with complex oligosaccharides, enhancing structural heterogeneity and facilitating surface expression. Phosphorylation sites are present on the intracellular C-terminus, contributing to agonist-induced desensitization by promoting interactions with regulatory proteins such as G protein-coupled receptor kinases. The receptor's molecular weight varies from approximately 50–80 kDa depending on the extent of glycosylation and other modifications, with the unglycosylated polypeptide core around 57 kDa for the α1B subtype.^[7]^[9]

Subtypes

The alpha-1 adrenergic receptors consist of three pharmacologically distinct subtypes, denoted α_1A, α_1B, and α_1D, each encoded by separate genes. The α_1A subtype is encoded by the ADRA1A gene located on chromosome 8p21.2.^[10] The α_1B subtype is encoded by the ADRA1B gene on chromosome 5q33.3.^[11] The α_1D subtype is encoded by the ADRA1D gene on chromosome 20p13.^[12] Tissue distribution of the subtypes exhibits selectivity, influencing their roles in various physiological processes. The α_1A subtype is predominantly expressed in the prostate, bladder, and resistance arteries such as mesenteric vessels, as well as in cardiac ventricular myocytes.^[13] The α_1B subtype is primarily found in vascular smooth muscle, including coronary arteries, myocardium, and abundantly in the central nervous system.^[13] The α_1D subtype predominates in large conductance arteries like the aorta and carotid, as well as in the brain (e.g., cerebral cortex) and ureter.^[13]^[5] Functional differences among the subtypes arise from their distinct expression patterns and signaling efficiencies. The α_1A subtype is linked to prostate smooth muscle contraction and hyperplasia, contributing to conditions like benign prostatic hyperplasia.^[13] The α_1B subtype mediates vasoconstriction in vascular smooth muscle and promotes cardiac hypertrophy.^[5] The α_1D subtype is associated with neural modulation, including neuronal growth and cerebellum development.^[12] Genetic variations in the subtype genes can influence receptor function and disease susceptibility. In the ADRA1A gene, the Arg347Cys polymorphism (rs1048101) has been associated with altered blood pressure responses and increased risk of hypertension, particularly in certain populations where the Cys allele carriers show greater systolic blood pressure reduction with α₁-antagonists.^[14]^[15] Polymorphisms across α₁ receptor genes, including in ADRA1A and ADRA1D, have also been linked to variations in autonomic control and orthostatic blood pressure dysregulation.^[16] The subtypes were molecularly cloned in the late 1980s and early 1990s, establishing their distinct identities. The hamster α_1B receptor was the first cloned in 1988, followed by human α_1B in 1990, human α_1A in 1991, and human α_1D (initially termed α_1C) in 1994.^[17] These efforts revealed high evolutionary conservation of the subtypes across vertebrates, with sequence identities exceeding 80% among mammalian orthologs, reflecting their fundamental roles in catecholamine signaling.^[18]

Signaling Mechanisms

G-protein Coupling

The alpha-1 adrenergic receptors (α1-ARs) primarily couple to the Gq/11 family of heterotrimeric G-proteins following agonist binding, such as norepinephrine or epinephrine. This interaction is a hallmark of their signaling as G protein-coupled receptors (GPCRs), where the bound agonist stabilizes an active receptor conformation that engages the G-protein heterotrimer composed of Gαq, Gβ, and Gγ subunits.^[19]^[1] The activation mechanism involves a ligand-induced conformational change in the receptor, which exposes the G-protein binding site primarily on the second and third intracellular loops (ICL2 and ICL3). These loops, along with the C-terminal tail, interact with the Gα subunit, promoting the exchange of GDP for GTP on Gαq. This nucleotide exchange induces dissociation of the Gαq-GTP from the Gβγ dimer, allowing both components to engage downstream effectors independently.^[19]^[1] Coupling specificity is predominantly to Gq/11 across the α1A, α1B, and α1D subtypes, though some reports indicate coupling to Gi/o under certain experimental conditions, such as in cell lines or overexpression models, particularly for the α1B subtype; however, this has not been demonstrated in vivo. Subtype differences can influence coupling efficiency, with variations in expression levels and tissue context modulating the interaction strength.^[19]^[1] Regulation of this coupling occurs through receptor desensitization, initiated by agonist-dependent phosphorylation of the receptor's C-terminal tail and intracellular loops by G protein-coupled receptor kinases (GRKs). This phosphorylation recruits β-arrestin, which sterically hinders further G-protein interaction and promotes receptor internalization, thereby attenuating signaling.^[19]^[1]

Intracellular Pathways

Upon ligand binding, alpha-1 adrenergic receptors (α1-ARs) primarily couple to heterotrimeric Gq/11 proteins, which activate phospholipase C-β (PLC-β) at the inner plasma membrane or nuclear envelope. This activation initiates the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) into the second messengers inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG).^[20]^[21] IP3 rapidly diffuses through the cytosol to bind IP3 receptors on the endoplasmic reticulum, opening calcium-permeable channels and releasing stored Ca²⁺ into the cytoplasm. This transient elevation in intracellular Ca²⁺ concentration serves as a key signaling hub for downstream effectors.^[20]^[21]^[22] In parallel, DAG remains embedded in the lipid bilayer and recruits protein kinase C (PKC) isoforms to the membrane, where Ca²⁺ further promotes their activation. Activated PKC then phosphorylates diverse substrates, including examples like myosin light chain, to modulate cellular responses such as contraction and secretion.^[23]^[21]^[24] The mobilized Ca²⁺ also binds calmodulin to form a Ca²⁺-calmodulin complex, which activates calcium-calmodulin-dependent kinases (CaMKs), particularly CaMKII, leading to phosphorylation events that amplify signaling and regulate processes like gene expression. Additionally, α1-AR stimulation engages the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) cascade, often through Gq/11 or β-arrestin mediation, to promote transcriptional activation and long-term cellular adaptations.^[22]^[25]^[22]^[25]^[26] α1-AR pathways exhibit crosstalk with the phosphoinositide 3-kinase (PI3K)/Akt axis, where PKC or Gq-derived signals intersect to activate PI3K, enhancing Akt phosphorylation and integrating pro-survival or hypertrophic responses. This convergence allows for nuanced regulation of cellular outcomes beyond the primary Gq-PLC axis.^[27]^[28]^[29]^[30]

Physiological Functions

Cardiovascular Effects

The α1-adrenergic receptors (α1-ARs), particularly the α1B subtype, play a central role in mediating vasoconstriction by enhancing vascular tone through calcium-dependent contraction of vascular smooth muscle cells. Upon activation by catecholamines such as norepinephrine, these receptors couple to Gq proteins, leading to phospholipase C activation, inositol trisphosphate production, and subsequent release of intracellular Ca²⁺ stores, which triggers myosin light chain phosphorylation and smooth muscle contraction. This mechanism contributes significantly to blood pressure regulation, for example, the α1D subtype contributes approximately 30-40% to the pressor response induced by norepinephrine in mice, as evidenced by reduced vasoconstrictive responses in α1D knockout models where other subtypes partially compensate.^[1]^[31]^[32] In the cardiovascular system, α1-AR activation is integral to the baroreflex, where hypotension triggers sympathetic nervous system outflow, releasing norepinephrine that binds α1-ARs on vascular smooth muscle to promote rapid vasoconstriction and restore arterial pressure. This sympathetic-mediated response helps maintain hemodynamic stability during orthostatic challenges or hypovolemia, with α1B-ARs specifically critical at the sympathetic neuroeffector junction for efficient transmission of vasoconstrictive signals.^[33]^[34] Cardiac effects of α1-ARs include positive inotropy (increased contractility) and chronotropy (increased heart rate) predominantly in atrial tissue, driven by enhanced Ca²⁺ handling and sarcoplasmic reticulum function. In ventricular myocytes, prolonged α1-AR stimulation via α1A and α1B subtypes induces physiological hypertrophy, characterized by increased cardiomyocyte size and protein synthesis without fibrosis, supporting adaptive growth under pressure overload. However, these cardiac responses exhibit species differences, with more pronounced inotropic and hypertrophic effects in rodents compared to humans, attributable to higher α1-AR density in rodent myocardium.^[35]^[36]^[31]

Smooth Muscle and Other Effects

In the genitourinary system, the α1A adrenergic receptor subtype predominates in the prostate stroma and bladder neck, where its activation by norepinephrine or epinephrine induces smooth muscle contraction essential for the emission phase of ejaculation and the closure of the bladder neck during micturition to prevent retrograde urine flow.^[37] This contractile response facilitates semen propulsion through the prostatic urethra and maintains urinary continence by increasing urethral resistance.^[38] Selective α1A antagonists, such as tamsulosin, are commonly used to relax these tissues in benign prostatic hyperplasia, thereby alleviating lower urinary tract symptoms while sometimes causing ejaculatory dysfunction as a side effect.^[39] In the gastrointestinal tract, α1 adrenergic receptors contribute to the contraction of sphincters, such as the internal anal sphincter and pyloric sphincter, enhancing tone and modulating motility by promoting closure to regulate the passage of contents.^[40] Activation of these receptors inhibits overall intestinal smooth muscle relaxation while specifically augmenting sphincter function, which aids in the control of defecation and gastric emptying.^[41] This selective enhancement of sphincter contraction helps maintain continence and compartmentalize digestive processes without broadly disrupting peristalsis. Pupillary dilation, or mydriasis, occurs through α1 adrenergic receptor activation in the iris dilator muscle, a radially oriented smooth muscle that contracts to increase the pupil's diameter in response to sympathetic stimulation.^[42] The α1A subtype is particularly implicated in this trophic and contractile effect, allowing adaptation to low-light conditions or arousal by widening the visual field.^[43] This mechanism is exploited clinically with α1 agonists like phenylephrine for diagnostic pupillometry.^[44] Metabolically, α1 adrenergic receptors in the liver promote glycogenolysis, the breakdown of glycogen to glucose, primarily through the α1A subtype, which triggers intracellular calcium release to activate phosphorylase kinase and mobilize glucose during stress responses.^[45] In adipose tissue, α1 receptor stimulation enhances lipolysis by increasing cyclic AMP-independent fatty acid release, contributing to energy mobilization under catecholaminergic influence, though this effect is secondary to β-adrenergic pathways.^[46] Platelets express α1-adrenergic receptors, which play a minor role in enhancing aggregation and secretion responses to catecholamines, potentially amplifying thrombus formation in high-shear conditions.^[47] This contribution is overshadowed by α2 receptors but may influence platelet reactivity in pathological states like hypertension.^[5]

Central Nervous System Roles

Alpha-1 adrenergic receptors (α1-ARs) are prominently distributed throughout the central nervous system, with high expression in the prefrontal cortex, hippocampus, and locus coeruleus, where α1B and α1D subtypes predominate alongside α1A. In the prefrontal cortex, α1-ARs, primarily α1A, are localized on pyramidal neurons and GABAergic interneurons, facilitating glutamatergic synaptic plasticity. The hippocampus exhibits dense α1A expression in the CA1, CA3, and dentate gyrus regions, supporting learning-dependent processes, while the locus coeruleus, the primary source of noradrenergic innervation, contains α1-ARs that regulate neuronal excitability and noradrenergic outflow. Overall, α1A constitutes approximately 55% of brain α1-ARs, α1B about 35%, and α1D around 10%, with mRNA studies confirming their presence in these areas across species like rats.^[1]^[4]^[48] These receptors play key roles in neuromodulation, enhancing arousal, attention, and memory consolidation through noradrenergic projections from the locus coeruleus. In the prefrontal cortex, α1-AR activation by norepinephrine improves working memory and attentional performance by boosting excitatory synaptic transmission and reducing distractibility. Within the hippocampus, α1A-ARs promote long-term potentiation (LTP) and synaptic plasticity, thereby aiding spatial and contextual memory formation. Arousal is further amplified via α1-AR-mediated glutamate release from astrocytes and modulation of ventral periaqueductal gray activity, contributing to heightened alertness during stress or novel stimuli.^[1]^[4]^[49] In the spinal cord, α1D-ARs are involved in locomotor control, particularly through their expression on motor neurons, where they facilitate stimulus-induced activity and reflex arcs essential for coordinated movement. These receptors also contribute to pain modulation in the dorsal horn by influencing glutamatergic sensory inputs, often exerting facilitatory effects that can amplify nociceptive signaling under certain conditions. Pathologically, α1-AR hyperactivity in the prefrontal cortex and basolateral amygdala is implicated in anxiety disorders and post-traumatic stress disorder (PTSD), where excessive noradrenergic tone disrupts cognitive flexibility and enhances fear memory consolidation; antagonists like prazosin mitigate these effects by blocking receptor activity.^[4]^[48]^[50] Subtype-specific functions highlight the diversity of α1-AR roles, with α1A-ARs in the hypothalamus regulating feeding behavior and glucose metabolism by modulating presynaptic noradrenergic inputs and promoting energy homeostasis. This hypothalamic involvement underscores α1A's broader influence on behavioral and metabolic integration within the CNS.^[1]^[4]

Ligands and Pharmacology

Endogenous and Selective Ligands

The endogenous ligands for the α1-adrenergic receptor are the catecholamines norepinephrine and epinephrine. Norepinephrine functions as the primary neurotransmitter released from postganglionic sympathetic neurons, whereas epinephrine is secreted from the adrenal medulla during stress responses.^[1]^[5] These ligands bind to the orthosteric site within the transmembrane domain of the receptor, where the protonated amine group forms an ionic interaction with Asp^{3.32} (e.g., Asp106 in α1A) in transmembrane helix 3, and the meta- and para-hydroxyl groups of the catechol ring engage in hydrogen bonding with Ser^{5.46} (e.g., Ser192 in α1A) and Ser^{5.43} (e.g., Ser188 in α1A) in transmembrane helix 5.^[2] Binding affinities for norepinephrine and epinephrine are typically in the low micromolar range, with reported Ki values of approximately 1.5–4.4 μM depending on the assay and tissue context.^[51]^[52] Norepinephrine and epinephrine display low selectivity among the α1 receptor subtypes (α1A, α1B, and α1D), exhibiting comparable binding affinities across them, though subtle preferences exist such as slightly higher affinity for α1A in certain vascular tissues.^[5]^[17] In contrast, phenylephrine serves as a selective α1 agonist, preferentially activating α1 receptors over α2 or β subtypes without significant intrinsic activity at the latter.^[53]^[54] No prominent endogenous antagonists directly compete at the orthosteric site of α1 receptors; instead, tonic regulation of receptor signaling occurs primarily through reuptake of norepinephrine by plasma membrane transporters such as the norepinephrine transporter (NET).^[4] Allosteric modulators of α1 receptors have been identified, including positive allosteric modulators that enhance agonist binding and efficacy at non-conserved sites; for instance, Compound 3 acts as a subtype-selective positive allosteric modulator at α1A receptors, potentiating norepinephrine responses without direct agonism.^[55]

Therapeutic Agents

Therapeutic agents targeting the alpha-1 adrenergic receptor primarily consist of synthetic agonists and antagonists used in clinical settings to modulate sympathetic nervous system activity. These compounds are designed to either activate or block alpha-1 receptors, influencing vascular tone, smooth muscle contraction, and blood pressure regulation. Agonists are employed to counteract hypotension, while antagonists are commonly prescribed for hypertension and benign prostatic hyperplasia (BPH).^[56] Midodrine serves as a key synthetic agonist, functioning as a prodrug that is metabolized to its active form, desglymidodrine, which selectively stimulates alpha-1 adrenergic receptors to induce peripheral vasoconstriction and elevate blood pressure. It is FDA-approved for treating symptomatic orthostatic hypotension, particularly in patients with autonomic dysfunction, by increasing systemic vascular resistance without significant cardiac stimulation. Pharmacokinetically, midodrine is administered orally with rapid absorption, reaching peak plasma concentrations within 30 minutes, and its active metabolite has a half-life of approximately 3-4 hours; it undergoes hepatic metabolism primarily via oxidation and is excreted renally. Common adverse effects include supine hypertension, piloerection (goosebumps), pruritus, urinary retention, and chills, which stem from its vasoconstrictive properties and necessitate monitoring to avoid excessive blood pressure elevation.^[57]^[58] Antagonists predominate in alpha-1 receptor pharmacotherapy, with non-selective and subtype-selective agents tailored for cardiovascular and urological applications. Prazosin, a non-selective alpha-1 antagonist acting on α1A, α1B, and α1D subtypes, is utilized for hypertension and BPH by relaxing vascular and prostatic smooth muscle, thereby reducing peripheral resistance and improving urinary flow. It exhibits a short half-life of 2-3 hours, with peak effects in 1-3 hours, and is extensively metabolized in the liver via CYP3A4-mediated demethylation and conjugation, followed by biliary and fecal excretion. Adverse effects, notably orthostatic hypotension and first-dose syncope due to non-selective blockade, require gradual dose titration starting at 1 mg.^[56]^[59]^[60] For enhanced uroselectivity, tamsulosin targets the α1A subtype predominantly expressed in the prostate and bladder neck, making it a first-line treatment for BPH symptoms with minimal impact on vascular α1B receptors. Its pharmacokinetics include a half-life of 9-13 hours, hepatic metabolism via CYP3A4 and CYP2D6, and once-daily dosing. Intraoperative floppy iris syndrome during cataract surgery and retrograde ejaculation are notable adverse effects, alongside milder dizziness. Silodosin, even more α1A-selective (with affinity ratios >25-fold over other subtypes), is similarly indicated for BPH and ureteral stone expulsion, boasting a half-life of about 13 hours and glucuronidation-based hepatic metabolism independent of major CYPs. It carries a higher risk of ejaculatory dysfunction (up to 28%) compared to tamsulosin, but lower cardiovascular side effects.^[56]^[61]^[62] Doxazosin, a long-acting non-selective alpha-1 antagonist similar to prazosin but with a prolonged half-life of approximately 22 hours, is prescribed for both hypertension and BPH, allowing once-daily administration and sustained blood pressure control. It is metabolized hepatically through O-demethylation and hydroxylation, primarily via CYP3A4. Like other non-selective agents, it predisposes patients to orthostatic hypotension, particularly in the elderly, though its extended duration reduces dosing frequency and improves adherence. Overall, selectivity profiles guide clinical choice: non-selective agents like prazosin and doxazosin for broader cardiovascular benefits, and uroselective ones like tamsulosin and silodosin to minimize hypotensive risks in urological therapy.^[56]^[63]

Clinical Relevance

Role in Disease

Dysregulation of alpha-1 adrenergic receptors (α1-ARs) contributes significantly to hypertension, primarily through overactive vasoconstriction mediated by the α1B subtype. In vascular smooth muscle, α1B-AR activation by norepinephrine and epinephrine increases intracellular calcium via Gq-protein coupling, leading to enhanced contractility and elevated peripheral resistance, which exacerbates blood pressure elevation. Studies in spontaneously hypertensive rats have shown increased α1-AR expression and autoantibodies against these receptors, promoting refractory vasoconstriction and linking overactivity to disease progression. Genetic variants in the ADRA1B gene, such as those identified in knockout mouse models, result in blunted blood pressure responses to agonists like phenylephrine (approximately 45% of normal), underscoring the subtype's role in baroreflex impairment and heightened hypertension risk in humans.^[1]^[1]^[1]^[64] In benign prostatic hyperplasia (BPH), upregulation of the α1A-AR subtype in prostatic smooth muscle drives dynamic obstruction of urinary flow. This receptor's increased expression, observed in both human prostate tissues and animal models, heightens sensitivity to catecholamines, inducing sustained contraction of the prostate and urethra, which compresses the bladder outlet and causes lower urinary tract symptoms like hesitancy and weak stream. Quantitative assessments in BPH patients reveal elevated α1A mRNA levels (e.g., 1.4 copies/ng β-actin pre-treatment, rising further with certain interventions), correlating with the severity of obstruction in cases without acute retention. This subtype predominance in the prostate—comprising up to 70% of α1-ARs—makes it a key pathological driver, distinct from static glandular enlargement.^[65]^[66]^[65]^[67] The role of α1A-ARs in heart failure is primarily cardioprotective: activation enhances myocardial contractility, reduces apoptosis, and induces physiological hypertrophy without fibrosis, as evidenced by improved ejection fractions in transgenic mice overexpressing the receptor. Human studies corroborate this, showing downregulated α1A-AR density in failing ventricles, which correlates with diminished adaptive responses to stress. This protective function highlights α1A-ARs as potential therapeutic targets, with agonists showing promise in mitigating post-infarct remodeling and necroptosis in cardiomyocytes. As of November 2025, phase II clinical trials of subtype-selective α1A-AR agonists demonstrate potential in reducing post-infarct remodeling.^[68]^[69]^[68]^[69]^[70]^[71] Alpha-1 ARs contribute to neurological disorders like attention-deficit/hyperactivity disorder (ADHD) and schizophrenia through impaired prefrontal cortical (PFC) function and hypofunction in noradrenergic signaling. In schizophrenia, heightened norepinephrine activity at α1-ARs in the PFC disrupts working memory and executive control, with postmortem studies revealing altered receptor density and associations with manic symptoms and cortical hypofunction. For ADHD, α1-AR co-localization with dopamine D1 receptors in PFC dendrites modulates attention and cognitive flexibility, where dysregulation leads to attentional deficits; genetic links to adrenergic pathways parallel those in schizophrenia models. These effects stem from α1-AR-mediated phospholipase C activation, influencing neuronal excitability and synaptic plasticity in hypofunctional circuits.^[72]^[73]^[72]^[74]^[73] Recent post-2019 research implicates α1-ARs in COVID-19-related vasoplegia via dysregulated catecholamine responses. In severe COVID-19, cytokine storms induce endothelial dysfunction and α1-AR desensitization, contributing to refractory vasoplegic shock where vasopressors like norepinephrine fail to restore vascular tone adequately, as seen in elevated requirements for α1-mediated vasoconstriction in critically ill patients. These insights emphasize α1-ARs in the maladaptive vascular sequelae of SARS-CoV-2.^[75]^[75]^[75]

Applications in Exercise Physiology

During exercise, a sympathetic nervous system surge activates α1-adrenergic receptors, promoting vasoconstriction in inactive vascular beds to redirect blood flow toward active skeletal muscles, thereby supporting increased metabolic demands and maintaining systemic blood pressure.^[76] This α1-mediated vasoconstriction is evident in both resting and exercising limbs, where intra-arterial administration of α1-agonists like phenylephrine reduces leg blood flow by approximately 10% at moderate intensities, though it is progressively attenuated (sympatholysis) in active muscles as exercise intensity rises due to local metabolic factors such as increased oxygen uptake.^[77] In untrained individuals, α1-adrenergic receptors contribute significantly to the pressor response during exercise, exacerbating blood pressure elevations through heightened postjunctional vasoconstrictor responsiveness and impaired functional sympatholysis, which limits the blunting of sympathetic tone in active tissues.^[78] This results in greater exercise-induced hypertension compared to trained states, where adaptations reduce α1 sensitivity, leading to more moderate blood pressure increments despite similar sympathetic activation levels. Endurance training induces downregulation of vascular α1-adrenergic receptor-mediated tone, enhancing arterial compliance by about 30-40% and reducing resting vascular resistance without altering nitric oxide-dependent mechanisms.^[79] Specifically, chronic aerobic exercise diminishes α1B subtype responsiveness in conduit arteries, contributing to lower basal vasoconstrictor tone and improved hemodynamic efficiency at rest. Post-exercise, transient hyporesponsiveness of α1-adrenergic receptors occurs, characterized by a 20-30% reduction in vasoconstrictor responses to agonists like phenylephrine, which is buffered by enhanced nitric oxide bioavailability and contributes to post-exercise hypotension lasting 1-2 hours. α1-adrenergic receptors in skeletal muscle support metabolic adaptations during high-intensity exercise by activating AMPK/PGC1α signaling pathways, promoting mitochondrial biogenesis and oxidative ATP production to mitigate oxidative stress and sustain energy supply.^[80] This receptor expression and activation increase under intense workloads, facilitating glucose uptake and fatty acid oxidation beyond what is seen in lower-intensity efforts.

References

[1]
Current Developments on the Role of α1-Adrenergic Receptors in ...
The α 1 -adrenergic receptors (ARs) are G-protein coupled receptors that bind the endogenous catecholamines, norepinephrine, and epinephrine.
[2]
Structure-Function of α1-Adrenergic Receptors - PubMed Central - NIH
α1-adrenergic receptors require a protonated amine, a β-hydroxyl on a chiral center, and an aromatic ring with hydrogen bonding substitutions, based on the ...
[3]
α1-Adrenergic Receptors in Neurotransmission, Synaptic Plasticity ...
α1-adrenergic receptors are G-protein coupled receptors involved in neurotransmission, regulating synaptic efficacy, plasticity, and memory. They are activated ...
[4]
α1-Adrenergic Receptor Subtypes | Circulation Research
α 1 ARs are activated by the catecholamines, norepinephrine and epinephrine. They are intrinsic membrane glycoproteins and are members of the GPCR superfamily.
[5]
G protein-coupled receptors (GPCRs): advances in structures ...
Apr 10, 2024 · Class A GPCRs, namely the rhodopsin-like family, is the superfamily with the largest proportion and the most extensive research. Class A GPCRs ...
[6]
Co- and Posttranslational Modification of the α1B-Adrenergic Receptor: Effects on Receptor Expression and Function†
### Summary of Post-Translational Modifications of α1B-Adrenergic Receptor
[7]
Crystal structure of the α1B-adrenergic receptor reveals molecular ...
Jan 19, 2022 · Here, we report the crystal structure of human α 1B AR bound to the inverse agonist (+)-cyclazosin, enabled by the fusion to a DARPin crystallization chaperone.
[8]
Alpha-1B adrenergic receptor - P35368 - UniProt
This alpha-adrenergic receptor mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system.
[9]
148 - Gene ResultADRA1A adrenoceptor alpha 1A [ (human)] - NCBI
Sep 5, 2025 · Alpha-1-adrenergic receptors (alpha-1-ARs) are members of the G protein-coupled receptor superfamily. They activate mitogenic responses and ...
[10]
147 - Gene ResultADRA1B adrenoceptor alpha 1B [ (human)] - NCBI
Aug 19, 2025 · Alpha-1-adrenergic receptors (alpha-1-ARs) are members of the G protein-coupled receptor superfamily. They activate mitogenic responses and ...
[11]
146 - Gene ResultADRA1D adrenoceptor alpha 1D [ (human)] - NCBI
Aug 19, 2025 · ADRA1D induces vascular smooth muscle apoptosis via a p53-dependent mechanism. expression in distal ureter higher than in proximal and mid ...
[12]
Updates in the function and regulation of α 1 -adrenoceptors
Feb 10, 2019 · This review article surveys the tissue distribution of the three α1-adrenoceptor subtypes in the cardiovascular system, genitourinary system ...Abstract · INTRODUCTION · INTRACELLULAR... · α1-ADRENOCEPTORS IN...
[13]
Association of alpha1a-adrenergic receptor polymorphism and ...
We aimed to investigate the association between the Arg347Cys polymorphism in the α 1A -AR gene and blood pressure phenotypes, in a large sample of Brazilians ...
[14]
Arg347Cys polymorphism of α1A-adrenoceptor gene is associated ...
May 15, 2009 · In this study, we showed that hypertensive patients carrying the Cys347 allele of the ADRA1A gene had a better SBP reduction in response to ...
[15]
Arg347Cys polymorphism of α1a-adrenergic receptor in vasovagal ...
Some studies have found a positive correlation between the Arg347Cys polymorphism of the α1a-adrenergic receptor to hypertension and heart autonomic control.
[16]
Adrenergic Receptors in Cognition, Cardioprotection, and Metabolism
The α1-adrenergic receptors (ARs) are G-protein coupled receptors that bind the endogenous catecholamines, norepinephrine, and epinephrine.
[17]
Evolutionary diversification and expressional profile of adrenergic ...
Oct 23, 2025 · CgA1AR-1 acts as an alpha-1 adrenergic receptor in oyster Crassostrea gigas mediating both cellular and humoral immune response. Fish ...
[18]
Cardiac Alpha1-Adrenergic Receptors: Novel Aspects of Expression ...
All three α1-ARs are G-protein-coupled receptors (GPCR), and classic α1-AR signaling mechanisms involve coupling to the Gq/11 (Gαq) family of G-proteins and ...
[19]
https://pmc.ncbi.nlm.nih.gov/articles/PMC3880467/
[20]
and alpha 1D-adrenergic receptor to multiple signaling pathways is ...
Coupling of expressed alpha 1B- and alpha 1D-adrenergic receptor to multiple signaling pathways is both G protein and cell type specific · Authors · Affiliation.
[21]
https://pubmed.ncbi.nlm.nih.gov/8232229/
[22]
https://pubmed.ncbi.nlm.nih.gov/24368739/
[23]
https://doi.org/10.1210/en.2004-1083
[24]
https://doi.org/10.1152/physrev.00023.2003
[25]
https://pubmed.ncbi.nlm.nih.gov/29175420/
[26]
https://doi.org/10.1016/j.cellsig.2004.10.008
[27]
https://doi.org/10.3389/fphys.2019.00055
[28]
https://pubmed.ncbi.nlm.nih.gov/30664381/
[29]
https://doi.org/10.1161/CIRCRESAHA.108.176024
[30]
Cardiac and Vascular α 1 -Adrenoceptors in Congestive Heart Failure
This complication is characterized by low systemic vascular resistance, severe hypotension ... alpha 1-adrenergic receptor subtype mRNA in rat tissues and human ...
[31]
The α1D-adrenergic receptor directly regulates arterial blood ... - NIH
Besides hypotension, the pressor responses to phenylephrine and norepinephrine were decreased by 30–40% in α1D–/– mice. Furthermore, the contractile response of ...
[32]
The sympathetic nervous system and blood pressure in humans
The autonomic nervous system and its sympathetic arm play important roles in the regulation of blood pressure.
[33]
Critical Role for the α-1B Adrenergic Receptor at the Sympathetic ...
The α-1 adrenergic receptors (α1ARs) are critical in sympathetically mediated vasoconstriction. The specific role of each α1AR subtype in regulating ...
[34]
Cardiac and Vascular α1-Adrenoceptors in Congestive Heart Failure
We have performed a systematic literature review examining the role of both cardiac and vascular α 1 -ARs in HF using 5 databases for our search.
[35]
and α1B-adrenergic receptors are required for physiological cardiac ...
Catecholamines and α1-adrenergic receptors (α1-ARs) cause cardiac hypertrophy in cultured myocytes and transgenic mice, but heart size is normal in single ...
[36]
α1-Adrenoceptor subtypes and lower urinary tract symptoms - PMC
This review summarizes α 1 AR subtypes, their mechanistic role in BPH and LUTS and data demonstrating effectiveness in LUTS management.
[37]
The role of benign prostatic hyperplasia treatments in ejaculatory ...
Alpha-1a receptors are located in the prostate, bladder neck, seminal vesicles, and vas deferens. Contraction of the smooth muscle in these locations leads to ...Missing: genitourinary | Show results with:genitourinary
[38]
Alpha1-adrenergic receptors and their inhibitors in lower urinary ...
Purpose: We provide a comprehensive overview of the role of alpha1-adrenergic receptors (alpha1ARs) as critical mediators of lower urinary tract symptoms ...
[39]
Characterization of the α1-adrenoceptor subtype mediating ... - NIH
The internal anal sphincter has been shown to contract in response to α1-adrenoceptor stimulation and therefore α1-adrenoceptor agonists may be useful in ...
[40]
Review article: adrenergic control of motor and secretory function in ...
Adrenoreceptor stimulation appears to reduce intestinal contraction (except at sphincters), both via alpha-receptors which inhibit neurotransmitter release ...
[41]
Role of α₁-adrenoceptor subtypes in pupil dilation studied with ...
Nov 25, 2014 · Purpose: The α₁A-adrenoceptor (α₁A-AR) subtype was suggested to mediate contraction and trophic effects in the iris dilator muscle, and thus its ...
[42]
Role of α1-Adrenoceptor Subtypes in Pupil Dilation Studied ... - IOVS
The α 1A -adrenoceptor (α 1A -AR) subtype was suggested to mediate contraction and trophic effects in the iris dilator muscle.
[43]
Mechanism of Action | RYZUMVI® (phentolamine ophthalmic solution)
Phenylephrine works by binding to the alpha-1 adrenergic receptors on the iris dilator muscle, causing the muscle to contract and pupil to dilate. This ...
[44]
Adrenergic G protein-coupled receptors in liver physiology ... - Nature
Oct 24, 2025 · The physiological role of α-ARs in the liver is primarily through regulating hepatic glycogen metabolism. The main mechanism by which the α1-AR ...Missing: 1A | Show results with:1A
[45]
In vivo alpha(1)-adrenergic lipolytic activity in subcutaneous adipose ...
These results demonstrate that alpha(1)-adrenoceptors are involved in regulation of lipolysis rate and microcirculation of adipose tissue.
[46]
The effects of alpha adrenergic agents on human platelet aggregation
The effects of alpha adrenergic agonists and antagonists on human in vitro platelet aggregation were studied to characterize further the platelet alpha ...Missing: 1D | Show results with:1D
[47]
https://pubmed.ncbi.nlm.nih.gov/34707/
[48]
https://pubmed.ncbi.nlm.nih.gov/12874602/
[49]
Descending pain modulation and chronification of pain - PMC
In contrast to the spinal α2-adrenergic receptors, activation of spinal α1-adrenergic receptors shows a pain facilitatory effect [92]. Spinal administration of ...Missing: arcs | Show results with:arcs
[50]
Structural basis of agonist specificity of α 1A -adrenergic receptor
Aug 10, 2023 · For example, the α1A-AR subtype is a vasopressor expressed in resistance arteries and is required for normal arterial blood pressure regulation.
[51]
https://pubmed.ncbi.nlm.nih.gov/6130152/
[52]
(-)-noradrenaline | Ligand Activity Charts
Binding affinity against alpha-1 adrenergic receptor in guinea pig cerebral cortical membranes by displacement of [3H]- WB-4101, B, 5.82, pKi, 1500, nM, Ki, J ...Missing: epinephrine | Show results with:epinephrine
[53]
Phenylephrine - StatPearls - NCBI Bookshelf - NIH
Oct 30, 2023 · Phenylephrine primarily acts as an alpha-1 adrenergic receptor agonist and exhibits minimal to no beta-adrenergic activity.
[54]
Rapid response to the alpha-1 adrenergic agent phenylephrine in ...
Nov 10, 2020 · Phenylephrine, a selective α1-adrenergic receptor agonist, is one of the most commonly used agents for the treatment of intraoperative ...
[55]
Characterization of a novel positive allosteric modulator of the ... - NIH
α1-ARs control various aspects of neurotransmission, cognition, cardiovascular functions as well as other organ systems. However, therapeutic drug development ...
[56]
Alpha-Blockers - StatPearls - NCBI Bookshelf - NIH
Feb 6, 2025 · Alpha-blockers are medications used to manage essential hypertension, benign prostatic hyperplasia, and pheochromocytoma.
[57]
Alpha-1 Receptor Agonists - StatPearls - NCBI Bookshelf - NIH
Jun 5, 2023 · Alpha-1 agonists are a class of medications used in the management of many disorders, including vasodilatory shock, hypotension, hypoperfusion, septic shock, ...
[58]
Midodrine: Uses, Interactions, Mechanism of Action | DrugBank Online
Midodrine may increase the bradycardic activities of Beractant. The risk or severity of adverse effects can be increased when Berahyaluronidase alfa is ...
[59]
Prazosin: Uses, Interactions, Mechanism of Action | DrugBank Online
This drug is mainly excreted in the bile and the feces Label. The plasma half-life is about 2-3 hours Label. In patients with congestive heart failure, the ...
[60]
Implications of Cytochrome P450 Interactions When Prescribing ...
Extensive metabolism by CYP3A4 in the intestinal mucosa and the liver ... Although drugs that block α1-receptors, such as prazosin hydrochloride and ...
[61]
Revisiting the Pharmacodynamic Uroselectivity of α 1 - PubMed
Tamsulosin and silodosin have the highest affinities for α 1A-AR, but only silodosin is clearly a selective α 1A-AR antagonist, with K i ratios of 25.3 and 50. ...
[62]
Silodosin: Uses, Interactions, Mechanism of Action | DrugBank Online
Silodosin is an alpha-1 adrenergic receptor antagonist used to treat symptoms associated with benign prostatic hyperplasia (BPH).Pharmacology · Interactions · Spectra<|control11|><|separator|>
[63]
Efficacy and safety of adrenergic alpha-1 receptor antagonists in ...
Sep 28, 2022 · This systematic review aims at presenting a complete overview of evidence over the benefits and risks of alpha-1 antagonist treatment in people ≥ 65 years.
[64]
GENETIC VARIATION IN THE ALPHA1B - ADRENERGIC ... - NIH
Alpha1A adrenergic receptors (α1A-ARs) are the prime mediators of vasoconstriction induced by activation of the sympathetic nervous system and thus play an ...Results · Hand Vein Study · Cold Pressor Test (cpt)
[65]
Up-regulation of α1a and α1d-adrenoceptors in the prostate by ...
We examined the correlation between the change in α(1)-adrenoceptor expression due to tamsulosin treatment and acute urinary retention during long-term followup ...Missing: obstruction | Show results with:obstruction
[66]
Impact of α-adrenoceptor antagonists on prostate cancer ...
α1-adrenoreceptor antagonists act to relieve BPH-LUTS by antagonizing the smooth muscle contractility induced by the catecholamine binding to α1A- ...
[67]
Phenotype pharmacology of lower urinary tract α1-adrenoceptors
Benign prostatic hyperplasia (BPH) is a common enlargement of the prostate gland that may lead to bladder outlet obstruction, and lower urinary tract symptoms.
[68]
Cardiac α1A-adrenergic receptors: emerging protective roles in ...
α1-AR SIGNALING PATHWAYS Activation of PLC generates the second messengers, inositol [1,4,5]-trisphosphate (IP3) and 2-diacylglycerol (DAG), ultimately ending ...
[69]
Alpha-1-Adrenergic Receptors in Heart Failure: The Adaptive Arm of ...
In the rodent and human heart, α1A and α1B-ARs are expressed predominantly in cardiac myocytes, whereas the α1D is found in coronary smooth muscle cells.
[70]
A (Alpha1-Adrenergic Receptors), B (Blocking ... - PubMed Central
Jan 22, 2024 · Gain-of-function studies in mice show that the beneficial effects of α1-ARs include: 1) physiological hypertrophy, mediated via protein kinase D ...
[71]
Cardiac and neuroprotection regulated by α1-adrenergic receptor ...
α1-Adrenergic receptor (AR) subtypes (α1A, α1B, and α1D) are G-protein-coupled receptors (GPCRs) that mediate the sympathetic nervous system by binding the ...
[72]
Adrenergic Pharmacology and Cognition: Focus on the Prefrontal ...
Introduction: Functions of the Prefrontal Cortex and Their Relevance to Mental Illness ... function in schizophrenia independently from change in psychosis ...
[73]
D1-dopamine and α1-adrenergic receptors co-localize in dendrites ...
Adrenergic targets for the treatment of cognitive deficits in schizophrenia. ... Role for the Cortical D-1 Dopamine Receptor. Eur J Neurosci. 1991;3:1001 ...D1-Dopamine And... · 1.2 Catecholamine Receptors... · 3. Results<|separator|>
[74]
Catecholamine physiology and its implications in patients with ...
Oct 28, 2020 · In this Personal View, we discuss the complex interplay between catecholamines and COVID-19, and the management of catecholamine excess states.
[75]
Regulation of Increased Blood Flow (Hyperemia) to Muscles During ...
For example, as a result of sympathetic vasoconstriction, renal and splanchnic blood flow can both fall to ∼25% of resting values during heavy exercise in ...
[76]
Role of α1-adrenergic vasoconstriction in the regulation of skeletal ...
α1-Adrenergic vasoconstriction during dynamic leg exercise is diminished in younger individuals, although the extent of this exercise-induced “sympatholysis” in ...
[77]
Exercise training modulates functional sympatholysis and α ...
Exercise training improves functional sympatholysis and reduces postjunctional α-adrenergic responsiveness in both normo- and hypertensive individuals.
[78]
Reduction in α-Adrenergic Receptor-Mediated Vascular Tone ...
We tested the hypothesis that the improved central arterial compliance with endurance training is mediated by decreased α-adrenergic tone and/or increased ...Missing: alpha1B downregulation<|separator|>
[79]
Stimulation of Alpha1‐Adrenergic Receptor Ameliorates Cellular ...
Feb 1, 2020 · Thus, the metabolic changes caused by α1-AR activation are almost the same as those caused by endurance exercise: simultaneously increasing the ...