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Threshold potential

The threshold potential is the critical membrane voltage in excitable cells, such as neurons and cardiac muscle cells, at which voltage-gated sodium channels sufficiently activate to trigger the rapid influx of sodium ions, initiating the depolarization phase of an action potential.^[1] In typical neurons, this threshold is reached at approximately -55 mV, a level that exceeds the resting membrane potential of about -70 mV and follows graded depolarizations from synaptic inputs or other stimuli.^[2]^[3] Once attained, the threshold potential sets off an all-or-none regenerative process, where the action potential propagates along the axon without decrement, enabling efficient signal transmission over long distances in the nervous system.^[1] This mechanism is fundamental to neuronal communication, sensory processing, and motor control, with the precise threshold value influenced by factors like ion channel density and local environmental conditions at sites such as the axon hillock.^[1] Variations in threshold potential can occur across cell types and physiological states, underscoring its role in modulating excitability and preventing spurious firing in response to subthreshold stimuli.^[2]

Definition and Fundamentals

Core Definition

The threshold potential is the critical membrane voltage level, approximately -55 mV (ranging from -60 to -50 mV) in neurons, at which voltage-gated sodium channels activate sufficiently to produce a net inward current that initiates the regenerative phase of an action potential.^[4]^[5] This level represents the point of instability in membrane excitability, where depolarizing stimuli overcome the stabilizing influences of potassium efflux and the sodium-potassium pump, leading to rapid self-amplifying depolarization.^[4] It is distinct from related concepts such as rheobase, defined as the minimal current amplitude of infinite duration required to depolarize the membrane to threshold, and chronaxie, the pulse duration needed to reach threshold using a current twice the rheobase value.^[6]^[7] These parameters quantify neuronal excitability in response to electrical stimuli and are foundational to understanding strength-duration relationships in excitable tissues.^[6] The threshold is characterized in strength-duration curves by the Lapicque-Weiss equation:

I = I_{\mathrm{rh}} \left(1 + \frac{\tau}{t}\right)

where I is the stimulus current amplitude, I_{\mathrm{rh}} is the rheobase current, t is the stimulus duration, and \tau is the chronaxie (typically around 0.1–1 ms in neurons).^[6]^[8] This hyperbolic relationship describes how shorter stimuli require higher currents to achieve threshold, reflecting the membrane's capacitive and resistive properties.^[6] From a typical resting membrane potential of -70 mV, the membrane must depolarize by approximately 10–20 mV to attain threshold, marking the transition from subthreshold graded potentials to the all-or-none action potential.^[9]

Role in Excitable Cells

The threshold potential functions as the critical "all-or-nothing" trigger for initiating action potentials in excitable cells, including neurons, cardiac myocytes, and skeletal muscle cells, where membrane depolarization must reach this specific voltage level to evoke a full response or none at all.^[10] In neurons, this threshold ensures that only stimuli strong enough to depolarize the membrane to approximately -55 mV will generate a propagating action potential, preventing weak signals from eliciting partial responses.^[4] Similarly, in cardiac myocytes, crossing the threshold around -70 mV triggers a complete action potential, while in skeletal muscle cells it is around -60 mV, linking electrical excitation directly to mechanical contraction.^[11]^[12] Reaching the threshold initiates rapid, self-sustaining depolarization that propagates signals reliably over long distances without decrement, enabling efficient communication in these cell types.^[10] In neurons, this propagation occurs along axons, often via saltatory conduction in myelinated fibers, ensuring swift transmission of nerve impulses from the central nervous system to effectors.^[4] For cardiac myocytes, threshold crossing in interconnected cells allows the action potential to spread across the myocardium, coordinating synchronized contractions essential for heart function.^[11] In skeletal muscle cells, the propagated action potential travels along the sarcolemma and into T-tubules, activating contraction throughout the fiber for precise motor control.^[12] This threshold mechanism is pivotal in neuronal synaptic transmission, where summed excitatory postsynaptic potentials at the axon hillock must exceed the threshold to fire an action potential, thereby relaying information across synapses to influence downstream neurons or muscles.^[4] In cardiac rhythm generation, pacemaker cells in the sinoatrial node spontaneously approach and cross their threshold during phase 4 depolarization, initiating each heartbeat and setting the pace for the entire conduction system.^[13] Overall, the threshold potential governs excitability, determining whether environmental stimuli translate into functional outputs like nerve signaling or muscle contractions.^[10]

Historical Development

Early Observations

In the 1840s, Emil du Bois-Reymond conducted extensive experiments on the electrical excitability of frog nerves, employing highly sensitive galvanometers to measure bioelectric currents and identify the minimal electrical stimulus required to produce a response. His work demonstrated that nerve excitation occurred only when the stimulus intensity exceeded a certain threshold, a finding detailed in publications such as his 1843 preliminary report on frog currents and his 1850 study on the laws of electrical nerve irritation. These observations established the electrical basis of nerve signaling and introduced quantitative aspects of stimulus thresholds in excitable tissues.^[14] Building on these foundations, early 19th-century experiments utilized galvanic stimulation—constant direct currents—to probe "irritability" thresholds in isolated muscle preparations, typically from frogs. Researchers like Carlo Matteucci applied varying current strengths to muscle-nerve setups, revealing that contractions ensued only above a minimal intensity, which varied with factors such as electrode placement and tissue condition. Matteucci's investigations in the 1830s and 1840s quantified these thresholds, linking electrical irritability to inherent tissue properties and advancing the understanding of excitation limits without invoking vitalistic forces.^[15] By 1902, Julius Bernstein integrated these insights into his seminal membrane theory, positing that cell membranes maintain a resting potential through selective permeability to potassium ions, with the threshold for excitation arising from a transient increase in permeability to other ions during stimulation. This model explained the all-or-nothing nature of nerve responses and preceded modern ion channel concepts by attributing threshold dynamics to permeability shifts rather than simple electrical breakdown. Bernstein's framework provided a biophysical rationale for the minimal stimuli observed earlier, influencing subsequent quantitative models of action potentials.^[16]

Key Experimental Discoveries

In the late 1920s and early 1930s, Joseph Erlanger and Herbert Spencer Gasser conducted pioneering electrophysiological studies on compound action potentials in mammalian nerve trunks, demonstrating that threshold potentials vary systematically with nerve fiber diameter. Using the cathode-ray oscillograph to record extracellular potentials, they classified fibers into groups (A, B, and C) based on conduction velocity and size, revealing that larger-diameter A-fibers exhibit lower excitation thresholds compared to smaller B- and C-fibers, which require stronger stimuli to initiate action potentials. This work highlighted threshold heterogeneity within nerve bundles, attributing variations to differences in fiber excitability and influencing subsequent models of nerve conduction. Building on these foundations, Alan Hodgkin and Andrew Huxley advanced the understanding of threshold potential through their voltage-clamp experiments on the squid giant axon in the early 1950s. By clamping the membrane potential to specific voltages and measuring ionic currents, they isolated the rapid inward sodium current responsible for depolarization, showing that threshold occurs at a membrane potential of approximately -57 mV (about 6-8 mV above the resting potential of -65 mV), where sodium influx begins to dominate and trigger regenerative excitation. These studies quantified the voltage- and time-dependent activation of sodium channels, establishing that threshold marks the instability point where positive feedback from sodium entry overcomes outward potassium and leak currents. Hodgkin and Huxley formalized these findings in a mathematical model that describes membrane dynamics at threshold, emphasizing the dominance of sodium conductance. The core equation governing the rate of change in membrane potential V is:

\frac{dV}{dt} = \frac{I - g_\mathrm{Na} m^3 h (V - E_\mathrm{Na}) - g_\mathrm{K} n^4 (V - E_\mathrm{K}) - g_\mathrm{L} (V - E_\mathrm{L})}{C_m}

where I is the applied current, g_\mathrm{Na}, g_\mathrm{K}, and g_\mathrm{L} are maximum conductances for sodium, potassium, and leak channels, m, h, and n are gating variables, E_\mathrm{Na}, E_\mathrm{K}, and E_\mathrm{L} are reversal potentials, and C_m is membrane capacitance. At threshold, the inward sodium term g_\mathrm{Na} m^3 h (V - E_\mathrm{Na}) rapidly increases due to voltage-dependent activation of m gates, driving dV/dt > 0 and initiating the action potential upstroke. This model accurately predicted action potential propagation and excitability, validated against experimental data from squid axons.

Biophysical Mechanisms

Resting Membrane Potential

The resting membrane potential represents the baseline electrical state of the cell membrane in excitable cells, such as neurons, typically maintained at approximately -70 mV, with the interior of the cell negative relative to the exterior.^[9] This potential arises primarily from the unequal distribution of ions across the membrane and the membrane's selective permeability to those ions, particularly potassium (K⁺).^[9] The sodium-potassium ATPase pump plays a crucial role in sustaining this potential by actively transporting three sodium ions (Na⁺) out of the cell and two potassium ions into the cell per cycle, counteracting passive ion leaks and establishing concentration gradients essential for the negative interior charge.^[17] The quantitative description of the resting membrane potential is provided by the Goldman-Hodgkin-Katz (GHK) voltage equation, which accounts for the contributions of multiple ions based on their permeabilities and concentration gradients:

V_m = \frac{RT}{F} \ln \left( \frac{P_K [K^+]_o + P_{Na} [Na^+]_o + P_{Cl} [Cl^-]_i}{P_K [K^+]_i + P_{Na} [Na^+]_i + P_{Cl} [Cl^-]_o} \right)

where V_m is the membrane potential, R is the gas constant, T is the absolute temperature, F is Faraday's constant, P denotes permeability coefficients, and subscripts o and i indicate extracellular and intracellular concentrations, respectively; note that chloride (Cl⁻) terms are inverted due to its negative charge. In typical neurons, the membrane's high permeability to K⁺ relative to Na⁺ and Cl⁻ (with P_K \gg P_{Na}) results in a resting potential close to the K⁺ equilibrium potential, around -90 mV, but shifted toward less negative values by minor Na⁺ influx.^[9] Leak channels, particularly potassium leak channels, are integral to stabilizing the resting potential by allowing passive K⁺ efflux, which generates the dominant negative charge inside the cell, while the Na⁺/K⁺ ATPase continuously restores ion gradients to prevent dissipation.^[9] This steady-state balance ensures the membrane remains polarized, serving as the essential starting point from which depolarizing stimuli can drive the potential toward threshold.^[9]

Depolarization Process

The depolarization process in excitable cells originates from the resting membrane potential, a stable state where the intracellular environment is negatively charged relative to the extracellular space, typically around -70 mV in neurons.^[18] This process is initiated by an external stimulus, such as a synaptic input or sensory signal, which triggers the opening of ligand-gated or mechanically sensitive ion channels, leading to an initial influx of positively charged ions—primarily sodium (Na⁺) in neurons or calcium (Ca²⁺) in certain muscle cells—into the cell.^[1]^[19] This selective permeability shift causes a gradual, partial depolarization, shifting the membrane potential from its resting value toward less negative levels, often by 5-15 mV depending on stimulus strength.^[20] As this initial depolarization progresses, the membrane voltage enters the activation range of voltage-gated ion channels embedded in the plasma membrane, prompting a small number of these channels—particularly voltage-gated Na⁺ channels—to transition from closed to open states.^[21] The resulting additional influx of Na⁺ ions further reduces the membrane's negative charge, creating a positive feedback loop where the rising voltage activates even more channels, exponentially increasing ion permeability and accelerating the depolarization rate.^[20] In cells relying on Ca²⁺, a similar mechanism operates through voltage-gated calcium channels, amplifying the inward current and driving the potential upward.^[19] The threshold potential, generally around -55 mV in neurons, marks the critical instability point in this sequence, where the positive feedback becomes self-sustaining and regenerative, ensuring the depolarization propagates as an all-or-nothing action potential without reverting to rest.^[1] At this juncture, the process transitions from stimulus-dependent to autonomous, as the cumulative ion influx overwhelms opposing forces like potassium efflux, committing the membrane to rapid overshoot.^[18] This regenerative nature distinguishes threshold from subthreshold depolarizations, which dissipate without full activation.^[20]

Ionic Currents at Threshold

At the threshold potential, typically around -50 to -55 mV in neuronal membranes, voltage-gated sodium channels undergo rapid activation, permitting a substantial influx of Na⁺ ions that drives regenerative depolarization and propels the membrane potential toward the overshoot phase of the action potential.^[1]^[22] This Na⁺ current, denoted as I_{Na}, dominates the ionic flux at this critical juncture, as the channels' activation gates open in response to the voltage shift, while their inactivation gates remain largely inactive initially.^[22] Contemporaneously, delayed rectifier potassium channels, characterized by their slower activation kinetics, begin to open but contribute minimally to the net current at threshold due to the opposing Na⁺ influx; these channels, modeled with activation variable n in the Hodgkin-Huxley framework, facilitate outward K⁺ flow that eventually counters depolarization.^[22] The inactivation gates of sodium channels, governed by the h variable, progressively close during this phase, curtailing further Na⁺ entry and thereby delineating the threshold boundary by preventing sustained excitation from subthreshold perturbations.^[22] The electrochemical gradients underlying these currents are quantified by the Nernst equation, which computes the equilibrium potential for each ion:

E_{\text{ion}} = \frac{RT}{zF} \ln \left( \frac{[\text{ion}]_o}{[\text{ion}]_i} \right)

where R is the gas constant, T is temperature in Kelvin, z is the ion's valence, and F is Faraday's constant.^[9] For Na⁺ in typical mammalian neurons, with extracellular concentration [\text{Na}^+]_o \approx 145 mM and intracellular [\text{Na}^+]_i \approx 12 mM at 37°C, E_{Na} \approx +60 mV, creating a strong inward driving force at threshold.^[9] In contrast, for K⁺ with [\text{K}^+]_o \approx 4 mM and [\text{K}^+]_i \approx 140 mM, E_K \approx -90 mV, resulting in negligible outward K⁺ current near threshold but poised for activation during peak depolarization.^[9]^[22]

Factors Influencing Threshold

Cellular Variations

The threshold potential exhibits notable variations across excitable cell types, largely attributable to differences in voltage-gated ion channel densities and subcellular architectures. In neurons, this value typically ranges from -50 to -40 mV, enabling rapid action potential initiation due to high densities of sodium channels, particularly at the axon initial segment.^[23] In contrast, cardiac myocytes display a lower threshold of -65 to -50 mV, resulting from comparatively reduced sodium channel densities that contribute to the distinct, slower depolarization kinetics observed in cardiac action potentials.^[24] Skeletal muscle fibers have a threshold potential around -55 mV, modulated by the intricate geometry of T-tubules, which influences membrane capacitance and the spatial distribution of voltage-sensitive channels to ensure synchronized excitation across the fiber.^[25]

Environmental and Pathophysiological Factors

Environmental factors such as hypoxia can modulate the threshold potential in neurons by altering ion channel function, thereby increasing cellular excitability. During hypoxic conditions, the voltage threshold for action potential initiation decreases, allowing neurons to fire with less synaptic input due to enhanced sodium influx through voltage-gated sodium channels. This shift is mediated by hypoxia-induced upregulation of sodium currents, which facilitates depolarization and lowers the membrane potential required to reach threshold.^[26]^[27] Similarly, hyperthermia influences neuronal threshold potential by promoting greater excitability through intrinsic membrane property changes. Elevated temperatures reduce the voltage threshold for action potential generation in both excitatory and inhibitory neurons, leading to faster depolarization rates and increased firing propensity via modulation of temperature-sensitive ion channels like TRPV4. This results in heightened neuronal responsiveness, as the membrane reaches firing threshold more readily under thermal stress.^[28]^[29] Pathophysiological alterations in extracellular ion concentrations, particularly hyperkalemia, affect threshold potential by depolarizing the resting membrane potential. Elevated extracellular potassium levels shift the resting potential toward less negative values (e.g., from -90 mV to -80 mV), partially inactivating voltage-gated sodium channels and effectively raising the threshold potential required for action potential initiation. This mechanism reduces neuronal excitability despite the initial depolarization, as the voltage difference between resting and threshold potentials narrows while sodium channel availability decreases.^[30]^[31] Genetic mutations, such as those in the SCN1A gene encoding the NaV1.1 sodium channel, can shift the threshold potential in affected neurons. Loss-of-function mutations in SCN1A, common in certain epilepsies, lead to higher thresholds for action potential firing by impairing sodium channel excitability, particularly in GABAergic interneurons. Computational models of these mutants demonstrate elevated voltage thresholds for single action potentials and repetitive firing, altering overall network dynamics without altering baseline cellular variations.^[32]

Measurement Techniques

Direct Recording Methods

Direct recording methods for threshold potential involve invasive electrophysiological techniques that enable precise measurement of the membrane voltage at which a regenerative action potential is initiated in isolated cellular preparations. These approaches typically employ current-clamp configurations to simulate natural depolarization while monitoring voltage responses, allowing researchers to identify the threshold as the point where sodium channel activation leads to an all-or-nothing spike rather than passive decay. Such methods are fundamental for studying excitability in neurons and other excitable cells, providing direct insight into the biophysical determinants of action potential firing. Intracellular microelectrode recordings represent a cornerstone technique, pioneered in the study of giant squid axons, where fine glass micropipettes filled with potassium chloride solution are inserted into the cell interior to both record membrane potential and inject current. Depolarizing current pulses of incrementally increasing amplitude are applied, and the threshold is determined as the membrane voltage at which the response transitions from a subthreshold electrotonic potential to a rapid upstroke driven by voltage-gated sodium influx, typically around -55 to -40 mV in mammalian neurons. This method allows for high-fidelity capture of the regenerative phase, revealing how threshold varies with stimulus ramp speed or holding potential, and has been instrumental in validating ionic models of excitability. For instance, in classic experiments, threshold was observed to shift with changes in external sodium concentration, confirming its dependence on inward currents. Brief applications of this approach also inform indirect methods like threshold electrotonus by establishing baseline excitability metrics in single fibers. Patch-clamp techniques, particularly whole-cell configurations in current-clamp mode, extend these measurements to smaller mammalian neurons and isolated cells where microelectrode impalement is challenging. A glass pipette forms a high-resistance seal on the cell membrane, enabling intracellular access without excessive damage; current steps are then injected to depolarize the membrane, and threshold is quantified as the voltage inflection point initiating the action potential overshoot. This variant offers superior space-clamp control, minimizing voltage escape in dendrites, and has quantified threshold values in diverse cell types, such as cortical pyramidal neurons at approximately -50 mV under physiological conditions. Advantages include low noise and the ability to dialyze the intracellular milieu for pharmacological studies, though series resistance artifacts must be compensated to ensure accurate threshold detection. Strength-duration curve plotting further refines threshold assessment by varying stimulus pulse width while measuring the minimal current required to elicit an action potential, often using the same intracellular or patch-clamp setups. The curve, typically hyperbolic, plots threshold current against duration on a semi-log scale, with rheobase defined as the minimal current for an infinitely long pulse, representing the steady-state threshold under constant depolarization. Seminal formulations describe this relationship as I_{th} = I_{rh} \left(1 + \frac{[\tau](/page/Tau)}{t}\right), where I_{th} is threshold current, I_{rh} is rheobase, \tau is the membrane time constant, and t is pulse duration; in neuronal preparations, rheobase currents range from 0.1 to 1 nA for intracellular stimulation. This analysis distinguishes passive membrane charging from active threshold crossing and is used to characterize excitability changes, such as hyperpolarizing shifts in threshold during repetitive firing.

Threshold Electrotonus Approach

The threshold electrotonus approach is a specialized electrophysiological technique designed to evaluate the threshold potential in intact peripheral nerve bundles without invasive intracellular recordings. Developed by Bostock and Baker, it employs automated threshold tracking to monitor changes in axonal excitability induced by prolonged subthreshold polarizing currents, typically lasting 100 ms, applied via surface electrodes.^[33] These currents, set at ±40% of threshold intensity, alter the membrane potential electrotonically, and the method continuously adjusts the test stimulus intensity to maintain a constant compound action potential amplitude, thereby tracking threshold variations over time.^[34] This non-invasive procedure allows assessment of multi-fiber nerve responses in vivo, providing insights into nodal and internodal membrane properties.^[34] Threshold electrotonus curves, derived from these measurements, plot the percentage change in threshold against time during the polarizing current. For depolarizing currents, the curves often display an S-shaped profile, characterized by an initial rapid rise (fast phase, peaking within 10-20 ms) followed by a transient decline and a slower secondary rise (slow phase, developing over 50-100 ms).^[34] These phases reflect the differential activation of fast and slow gating mechanisms, primarily involving voltage-dependent potassium channels that modulate sodium channel availability and membrane accommodation.^[33] Hyperpolarizing currents produce opposing shifts, with an initial decrease in threshold followed by an overshoot, highlighting inward rectifier properties.^[34] In clinical applications, threshold electrotonus is particularly useful for detecting subtle axonal dysfunction in conditions affecting nerve excitability, such as demyelination or channelopathies, by quantifying deviations in curve morphology.^[34] For instance, analysis of TE peaks can reveal abnormal threshold changes, with typical normal depolarizing shifts of 10-20% in the late phase indicating intact slow gating; reductions or exaggerations in these values signal impaired ion channel function or membrane polarization.^[34] This quantitative profiling, often implemented using systems like QTRAC, enables early diagnosis and monitoring of peripheral neuropathies through standardized protocols.^[34]

Clinical Relevance

Neurological Disorders

Altered threshold potential plays a significant role in the pathophysiology of several neurological disorders, where disruptions in neuronal excitability contribute to disease progression. In febrile seizures, which predominantly affect children aged 6 months to 5 years, elevated body temperature during fever lowers the activation threshold for neuronal firing, promoting hyperexcitability and synchronized activity that can precipitate seizures. This temperature-dependent reduction in threshold is evidenced by studies showing that hyperthermia increases the excitability of hippocampal pyramidal cells, dentate granule cells, and inhibitory interneurons, thereby enhancing the likelihood of seizure induction.^[35] Furthermore, lower fever temperatures are associated with a higher risk of seizure recurrence, indicating a dynamically reduced threshold in susceptible individuals.^[35] Mechanisms involve fever-induced changes in ion channel function, such as modulation of hyperpolarization-activated currents (I_h) via HCN channels, which amplify rebound depolarization and network excitability during prolonged episodes.^[36] In amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disease targeting motor neurons, reduced threshold potential in affected cells arises from sodium channel hyperactivity, leading to early hyperexcitability that exacerbates neuronal loss. Persistent sodium currents (I_NaP) are elevated in ALS motor neurons, particularly through upregulation of NaV1.6 at axon initial segments and hyperpolarizing shifts in NaV1.3 activation, which lower the voltage threshold for action potential initiation.^[37] This hyperactivity, observed in both SOD1 mutant mouse models and patient-derived neurons, contributes to repetitive firing and cortical hyperexcitability detectable even presymptomatically.^[37] The imbalance is compounded by reduced potassium channel expression, such as KCNQ2, failing to counteract sodium influx and further promoting excitotoxicity.^[37] Diabetes-related neuropathy, a common complication of chronic hyperglycemia, involves shifts in threshold potential driven by oxidative stress on voltage-gated sodium channels, resulting in sensory neuron hyperexcitability and neuropathic pain. Hyperglycemia upregulates NaV1.3 and NaV1.7 in dorsal root ganglion neurons, causing a negative shift in voltage-dependent activation and delayed inactivation of tetrodotoxin-sensitive currents, which lowers the threshold for action potential generation.^[38] Oxidative stress from reactive oxygen species further modifies channel function, such as reducing NaV1.8 peak currents while enhancing overall excitability through post-translational changes.^[38] Byproducts like methylglyoxal, generated under hyperglycemic conditions, directly activate NaV1.8, amplifying nociceptive signaling and contributing to hyperalgesia and allodynia.^[39]

Cardiovascular Conditions

In long QT syndrome (LQTS), delayed repolarization due to genetic mutations in ion channels, such as those affecting potassium or sodium currents, prolongs the action potential duration in ventricular cardiomyocytes, creating a substrate for early afterdepolarizations (EADs) that can reach the threshold potential and trigger torsades de pointes.^[40] This prolongation extends the vulnerable window during which premature stimuli are more likely to evoke re-excitation, as demonstrated in murine models where LQTS variants lower the re-excitation threshold at longer coupling intervals compared to controls.^[41] Consequently, the altered excitability dynamics in LQTS heighten the risk of polymorphic ventricular tachycardia, with clinical manifestations often linked to adrenergic triggers that exacerbate repolarization instability.^[42] Myocardial ischemia lowers the stimulation threshold in ventricular myocytes primarily through extracellular potassium accumulation and acidosis, which depolarize the resting membrane potential and enhance excitability early in the ischemic process. This reduction in threshold facilitates the initiation of ectopic beats and reentrant circuits, promoting the transition to ventricular fibrillation, particularly when combined with conduction slowing in the ischemic border zone.^[43] Studies in isolated perfused hearts show that this threshold decrease occurs transiently at potassium levels below 6 mmol/L, underscoring ischemia's role in acute arrhythmogenesis during coronary occlusion.^[44] In atrial fibrillation (AF), heterogeneous threshold changes across atrial tissue arise from regional variations in ion channel expression and remodeling, leading to nonuniform refractoriness that sustains reentrant wavefronts.^[45] Such heterogeneity, often exacerbated by persistent Na+ current increases, creates areas of differential excitability where action potential duration dispersion drives rotor formation and AF maintenance, as evidenced in genetic mouse models.^[46] This spatial variability in threshold recovery contributes to the self-perpetuating nature of AF, with pharmacological interventions targeting APD uniformity showing potential to reduce inducibility.^[47]

Therapeutic Interventions

Therapeutic interventions targeting threshold potential primarily involve pharmacological agents that modulate ion channel function to alter neuronal and cardiac excitability, as well as dietary strategies to influence electrolyte balance. Voltage-gated sodium channel blockers, such as carbamazepine, increase the threshold potential for action potential initiation by stabilizing inactivated sodium channels and reducing repetitive firing in hyperexcitable tissues.^[48] This mechanism prevents seizures in epilepsy by elevating the stimulus intensity required to elicit motor responses, as demonstrated in transcranial magnetic stimulation studies where carbamazepine raised motor thresholds by approximately 5% compared to placebo.^[48] Similarly, in cardiac contexts, class I antiarrhythmics like these blockers raise the threshold potential to suppress re-entrant arrhythmias, particularly in conditions such as ventricular tachycardia.^[49] Lidocaine, a class Ib sodium channel blocker, specifically stabilizes threshold potential in ischemic myocardial tissue by preferentially binding to inactivated sodium channels under acidic and depolarized conditions prevalent during ischemia.^[50] This action prolongs the effective refractory period and elevates the ventricular fibrillatory threshold, reducing the incidence of life-threatening ventricular arrhythmias at therapeutic plasma levels of 1.5–5 μg/mL.^[50] Clinical evidence supports its use in acute ischemic settings to interrupt re-entrant circuits, though its role has diminished with newer agents due to limited efficacy in non-ischemic arrhythmias.^[50] Dietary interventions play a supportive role in modulating threshold potential through electrolyte homeostasis, particularly in conditions involving potassium dysregulation. In hyperkalemia-related cardiac conditions, such as those complicating arrhythmias, restricting potassium intake via low-potassium diets helps normalize extracellular potassium levels, thereby restoring resting membrane potential and threshold excitability to prevent conduction abnormalities.^[51] Moderate hyperkalemia initially lowers the difference between resting and threshold potentials, heightening excitability, while severe levels inactivate sodium channels and elevate the effective threshold; dietary restriction aids in reversing these shifts to maintain stable cardiac rhythm.^[51] Additionally, omega-3 polyunsaturated fatty acids from dietary sources like fish oil modulate cardiac ion channel function, including sodium channels, to increase the threshold for membrane depolarization and reduce arrhythmogenic potential in ischemic heart disease. Supplementation with eicosapentaenoic and docosahexaenoic acids has been shown to inhibit sodium influx, thereby stabilizing action potentials and conferring cardioprotective effects against ventricular arrhythmias.^[52]

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These facts suggest that an increase in the temperature of neuronal tissue could enhance the rate, magnitude or synchrony of neuronal firing, leading to ...Missing: elevated | Show results with:elevated
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Voltage-gated sodium channels (Na V ) are the main contributors to action potential generation and essential players in establishing neuronal excitability.
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Ion channel disorders are an important cause of painful diabetic neuropathy. Drugs that target ion channels can be used to treat painful diabetic neuropathy.
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Is Long QT Syndrome a Disease of Abnormal Mechanical ...
Is Long QT Syndrome ... When early afterdepolarizations exceed threshold potential, they can elicit ectopic triggering beats that initiate Torsade de Points.
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The basis of ischemic arrhythmogenesis is alteration in the electrical properties of ventricular tissue, leading to changes in action potential conduction.
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A temporary decrease of the diastolic stimulation threshold during regional ischemia occurred at an average [K'], of <6.0+0.61 mmol/l (equivalent to a ...
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Conclusions—Atrial tachycardia causes nonuniform remodeling of atrial refractoriness that plays an important role in increasing atrial vulnerability to AF ...
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Hyperkalemia also depolarizes resting membrane potential, which first accelerates but then slows CV at [K+]o >8 mmol/l, manifested electrocardiographically by ...