Resting potential
The resting membrane potential, often simply called the resting potential, is the electrical potential difference across the plasma membrane of a quiescent cell, such as a neuron or muscle cell, when it is not actively transmitting signals.[1] This potential typically measures between -70 and -80 millivolts (mV) in neurons, with the intracellular side being negative relative to the extracellular side.[1] It arises primarily from the uneven distribution of ions across the membrane and the selective permeability of the membrane to those ions, establishing a baseline electrical state essential for cellular excitability and signal propagation.[2] The resting potential is maintained by the combined effects of ion concentration gradients and the membrane's higher permeability to potassium (K⁺) ions compared to sodium (Na⁺) or chloride (Cl⁻).[3] At rest, K⁺ ions leak out through open potassium channels, driven by their electrochemical gradient, which leaves the cell interior more negative due to the efflux of positive charge.[4] Meanwhile, Na⁺ and Cl⁻ ions are more concentrated outside the cell, but the membrane's low permeability to them at rest limits their influence, though minor Na⁺ influx contributes slightly to depolarizing the potential from the K⁺ equilibrium value of about -90 mV.[3] Calcium (Ca²⁺) ions also play a role in some cells but are less prominent in establishing the neuronal resting state.[5] These ion gradients are actively sustained by the sodium-potassium pump (Na⁺/K⁺-ATPase), an enzyme that hydrolyzes ATP to transport three Na⁺ ions out of the cell for every two K⁺ ions pumped in, counteracting passive leaks and generating a small electrogenic current that hyperpolarizes the membrane.[1] This pump ensures long-term stability of the resting potential, which is crucial for preventing osmotic swelling and enabling rapid changes during action potentials.[6] Disruptions in the resting potential, such as those caused by ion channel disorders or toxins, can lead to pathological conditions like hyperexcitability in epilepsy or muscle weakness in periodic paralyses.[1]Fundamentals
Definition and Physiological Importance
The resting membrane potential (RMP) is the electrical potential difference across the plasma membrane of a quiescent excitable cell, typically ranging from -60 to -80 mV with the intracellular side negative relative to the extracellular environment.[1] This baseline voltage represents the steady-state condition when the cell is not actively transmitting signals or contracting.[1] Physiologically, the RMP is crucial for enabling action potentials in excitable cells such as neurons and muscle cells, allowing rapid electrical signaling for nerve impulse propagation and coordinated muscle contraction.[1] In neurons, it establishes a stable threshold that prevents spontaneous firing, ensuring signals occur only in response to adequate stimuli.[4] Beyond excitability, the RMP contributes to ion balance that maintains cell volume and osmotic stability across various cell types.[7] In non-excitable cells, the RMP influences essential processes like nutrient uptake and secretion; for instance, in epithelial cells, it facilitates ion-dependent transport mechanisms that support absorption and osmotic balance.[7] This role underscores the RMP's broader importance in cellular homeostasis, independent of action potential generation.[7] The RMP arises primarily from ion concentration gradients of K⁺, Na⁺, and Cl⁻, coupled with the membrane's selective permeability to these ions.[1]Electroneutrality Principle
The electroneutrality principle states that the bulk intracellular and extracellular fluids of a cell are electrically neutral, with the sum of positive charges equaling the sum of negative charges in each compartment, preventing any macroscopic net charge imbalance.[8] This neutrality arises from the presence of diverse ions and charged molecules that balance each other, such as cations like K⁺ and Na⁺ counterbalanced by anions like Cl⁻ and organic phosphates. However, the resting membrane potential emerges from a localized separation of charges confined to a thin layer at the membrane interface, where positive charges accumulate on one side and negative on the other, without disrupting the overall neutrality of the larger fluid volumes.[9] The implications of this principle are profound for cellular electrophysiology: the charge separation necessary to generate a typical resting potential of around -70 mV is minuscule, approximately 6 × 10^{-13} mol/cm² for a membrane capacitance of 1 μF/cm², representing far less than 1/40,000th of the bulk intracellular K⁺ concentration. This negligible quantity ensures that no significant net charge builds up in the cell's interior or exterior, avoiding osmotic or electrostatic instabilities that could disrupt cellular function.[8] In contrast, total ion concentrations in these compartments hover around 150 mM, dwarfing the separated charges and underscoring how electroneutrality maintains homeostasis despite the voltage gradient. The cell membrane itself behaves as a capacitor in this context, storing the separated charges across its lipid bilayer, which acts as an insulator between the conductive intracellular and extracellular fluids.[10] The capacitance C of the membrane is conceptually described by the formula C = \frac{\varepsilon A}{d}, where \varepsilon is the permittivity of the membrane material, A is the membrane surface area, and d is its thickness (typically 5-10 nm).[10] This capacitive property allows the potential to be sustained with minimal charge displacement, as the electric field is concentrated within the thin dielectric layer. A common misconception is that the existence of a transmembrane potential violates electroneutrality, but in reality, the principle holds firmly because the charge imbalance is strictly surface-limited, occurring over Debye lengths of about 1 nm in physiological solutions (e.g., 0.1 M KCl), while bulk neutrality is restored almost instantaneously (on the order of 1 ns) through ion diffusion.[11] This localized separation enables the potential difference without compromising the electrical stability of the cell's volumes.[8]Ion Distribution and Maintenance
Intracellular and Extracellular Ion Concentrations
The resting potential of cells, particularly neurons, arises from steep concentration gradients of ions across the plasma membrane, with potassium (K⁺), sodium (Na⁺), and chloride (Cl⁻) playing dominant roles, alongside minor contributions from calcium (Ca²⁺) and impermeable organic anions (A⁻) such as proteins and phosphates.[12] Intracellularly, K⁺ is highly concentrated, while Na⁺ and Cl⁻ are low; extracellularly, the opposite holds true, creating diffusive forces that are counterbalanced by the membrane potential.[13] These gradients are not uniform across all cell types or species but follow a conserved pattern in mammalian neurons, as summarized in the table below for typical values.| Ion | Extracellular Concentration (mM) | Intracellular Concentration (mM) | Ratio (out/in) |
|---|---|---|---|
| Na⁺ | 145 | 12 | 12 |
| K⁺ | 5 | 140 | 0.036 |
| Cl⁻ | 110 | 7 | 15.7 |
| Ca²⁺ | 1.5 | 0.0001 | 15,000 |
| A⁻ (organic anions) | ~10 | ~140 | 0.07 |
Role of the Sodium-Potassium Pump
The sodium-potassium pump, also known as Na⁺/K⁺-ATPase, is an active transport protein embedded in the cell membrane that hydrolyzes ATP to move ions against their concentration gradients, thereby establishing the unequal distribution of sodium and potassium ions across the plasma membrane essential for maintaining the resting membrane potential (RMP).[21] In its operational cycle, the pump undergoes conformational changes between E1 (inward-facing) and E2 (outward-facing) states: in the E1 state, it binds three intracellular Na⁺ ions with high affinity, phosphorylates via ATP, and flips to the E2 state to release them extracellularly; subsequently, it binds two extracellular K⁺ ions, dephosphorylates, and returns to the E1 state to transport K⁺ inward.[21] This stoichiometry—three Na⁺ extruded for every two K⁺ imported per ATP molecule hydrolyzed—results in a net translocation of one positive charge out of the cell per cycle, rendering the pump electrogenic.[22] The electrogenic nature of the Na⁺/K⁺-ATPase directly hyperpolarizes the membrane by generating a small outward current, contributing approximately -5 to -10 mV to the RMP in typical neurons, where the overall RMP is around -70 mV.[23] However, this direct effect is minor compared to the pump's primary indirect role: by sustaining steep Na⁺ and K⁺ gradients (high extracellular Na⁺ and intracellular K⁺), it enables passive K⁺ efflux through leak channels, which dominates the RMP via the electrochemical equilibrium.[24] Without continuous pump activity, these gradients would dissipate due to ongoing passive ion fluxes, leading to loss of the negative intracellular potential.[21] In terms of energy demands, the Na⁺/K⁺-ATPase accounts for 20-40% of a neuron's total ATP consumption at rest, underscoring its metabolic burden in maintaining ion homeostasis amid constant leak currents.[24] This high energy cost reflects the pump's necessity in excitable cells, where even basal activity supports readiness for action potentials, and activity-induced Na⁺ influx amplifies ATP hydrolysis to restore gradients post-firing.[25] Inhibition of the pump, such as by cardiac glycosides like ouabain, initially blocks the electrogenic current, causing a rapid 5-8 mV depolarization, but prolonged exposure leads to Na⁺ accumulation intracellularly and K⁺ depletion extracellularly, resulting in gradient rundown and further progressive depolarization over minutes to hours.[23] This rundown disrupts the RMP irreversibly without intervention, highlighting the pump's indispensable role in long-term membrane stability.[21]Membrane Permeability and Transport
Ion Channels and Selective Permeability
At rest, the plasma membrane of excitable cells exhibits high permeability to potassium ions (K⁺) primarily through voltage-independent leak channels, which vastly outnumber those for sodium (Na⁺) and chloride (Cl⁻) ions, thereby dominating the resting membrane potential.[1] These leak channels, particularly from the two-pore domain potassium (K₂P) family, generate background K⁺ currents that stabilize the membrane at a negative potential by allowing passive K⁺ efflux down its electrochemical gradient.[26] In contrast, Na⁺ and Cl⁻ permeabilities remain low due to fewer open channels for these ions, preventing significant influx that could depolarize the membrane.[1] K₂P channels are dimeric proteins with two pore-forming domains each, forming a structure analogous to tetrameric potassium channels, and feature a selectivity filter composed of the conserved TVGYG amino acid sequence that ensures high K⁺ selectivity by coordinating dehydrated K⁺ ions. This filter, lined by carbonyl oxygen atoms, mimics the hydration shell of K⁺, allowing rapid conduction while rejecting Na⁺ due to its smaller size and higher hydration energy. Unlike voltage-gated channels, K₂P leak channels operate constitutively at resting potentials, maintaining a steady-state permeability without requiring activation.[26] In typical neurons, the relative permeabilities are approximately P_K : P_Na : P_Cl = 1 : 0.04 : 0.45, reflecting the predominance of K⁺ leak pathways over the minor contributions from Na⁺ and Cl⁻ channels.[27] These ratios ensure that the resting potential aligns closely with the K⁺ equilibrium potential while being slightly influenced by Na⁺ leak.[27] While K₂P channels experience minor modulation by intracellular factors such as pH and ATP in the basal state, their primary role remains providing consistent leak conductance to sustain the resting potential.[26]Active and Passive Transport Mechanisms
Passive transport mechanisms in the maintenance of resting membrane potential primarily involve facilitated diffusion through ion channels, which allow ions to move down their electrochemical gradients without direct energy expenditure. These channels, such as potassium leak channels, enable a high permeability to K⁺ ions, permitting their efflux from the cell and contributing significantly to the negative intracellular potential. Chloride channels also play a role by facilitating Cl⁻ movement, though their contribution is generally less pronounced than that of K⁺ channels in most neurons and muscle cells.[12] Active transport mechanisms counterbalance these passive fluxes to sustain ion gradients essential for the resting state. Primary active transport is exemplified by the Na⁺/K⁺-ATPase, which uses ATP hydrolysis to extrude Na⁺ and import K⁺, thereby preserving the asymmetry that underlies the potential. Secondary active transport, such as the Na⁺/Ca²⁺ exchanger, utilizes the Na⁺ gradient established by the primary pump to export Ca²⁺, exerting a minor influence on the resting membrane potential under normal conditions.[28][29] At steady state, the resting membrane potential arises from the integration of these mechanisms, where passive ion fluxes through channels are precisely balanced by active transport, resulting in a net zero current across the membrane. This equilibrium ensures stability, with the electrogenic nature of the Na⁺/K⁺ pump providing a small direct hyperpolarizing contribution.[28] Beyond ion-specific transporters, diversity in membrane transport includes aquaporins, which facilitate passive water movement and indirectly influence resting potential by modulating cell volume and thereby affecting ion dynamics, though their role is secondary to direct ion channels and pumps.[30]Theoretical Models
Nernst Equilibrium Potential
The Nernst equilibrium potential, also known as the Nernst potential, represents the membrane voltage at which there is no net flow of a specific ion across a semipermeable membrane, as the diffusive force due to the ion's concentration gradient is exactly balanced by the electrical force from the potential difference. This concept was originally derived by German physical chemist Walther Nernst in 1889 as part of his work on electrochemical equilibria.[31] In the context of cellular membranes, it provides the theoretical potential for individual ions like potassium (K⁺), sodium (Na⁺), or chloride (Cl⁻) if the membrane were selectively permeable to only that ion.[1] The derivation begins from the condition of zero net flux for the ion at equilibrium. The diffusive flux is proportional to the concentration gradient, given by Fick's law as J_{\text{diff}} = -D \frac{dc}{dx}, where D is the diffusion coefficient and c is concentration. The electrical flux arises from the drift under the electric field, J_{\text{elec}} = -u c \frac{d\psi}{dx}, where u is the mobility and \psi is the electrical potential. At equilibrium, these fluxes balance: D \frac{dc}{dx} = u c \frac{d\psi}{dx}. Using the Nernst-Einstein relation, which links diffusion and mobility via D = u \frac{RT}{zF} (where R is the gas constant, T is absolute temperature, z is ion valence, and F is Faraday's constant), integration across the membrane yields the equilibrium potential.[32] The resulting Nernst equation is: E_{\text{ion}} = \frac{RT}{zF} \ln \left( \frac{[\text{ion}]_{\text{out}}}{[\text{ion}]_{\text{in}}} \right) At physiological temperature (37°C or 310 K), this simplifies to the base-10 logarithmic form: E_{\text{ion}} = \frac{61.5}{z} \log_{10} \left( \frac{[\text{ion}]_{\text{out}}}{[\text{ion}]_{\text{in}}} \right) \quad \text{(in mV)} For example, using typical neuronal concentrations of [K⁺]ₒᵤₜ ≈ 4 mM and [K⁺]ᵢₙ ≈ 140 mM, the potassium equilibrium potential is approximately -90 mV. Similarly, for sodium with [Na⁺]ₒᵤₜ ≈ 145 mM and [Na⁺]ᵢₙ ≈ 12 mM, Eₙₐ ≈ +60 mV; and for chloride with [Cl⁻]ₒᵤₜ ≈ 110 mM and [Cl⁻]ᵢₙ ≈ 7 mM, E₍₍ ≈ -70 mV.[1] These values illustrate how concentration gradients, maintained by active transport mechanisms, dictate the direction and magnitude of potential for each ion.[1] The Nernst equation assumes the membrane is permeable exclusively to the ion in question, with no contributions from other species or active transport, making it ideal for isolated ion studies but limited in describing real membranes with multiple permeabilities.[32]Goldman-Hodgkin-Katz Voltage Equation
The Goldman-Hodgkin-Katz (GHK) voltage equation provides a theoretical framework for calculating the resting membrane potential (V_m) by accounting for the contributions of multiple permeant ions, weighted by their relative permeabilities across the cell membrane.[33] Originally derived from the constant field theory proposed by Goldman in 1943, the equation was adapted and experimentally validated by Hodgkin and Katz in 1949 using squid giant axon data to explain how sodium permeability influences the resting potential.[34] For monovalent ions such as potassium (K⁺), sodium (Na⁺), and chloride (Cl⁻), the GHK equation is expressed as: V_m = \frac{RT}{F} \ln \left( \frac{P_K [K^+]_{out} + P_{Na} [Na^+]_{out} + P_{Cl} [Cl^-]_{in}}{P_K [K^+]_{in} + P_{Na} [Na^+]_{in} + P_{Cl} [Cl^-]_{out}} \right) where R is the gas constant, T is the absolute temperature, F is Faraday's constant, P denotes the permeability coefficient for each ion, and subscripts "in" and "out" refer to intracellular and extracellular concentrations, respectively.[33] Note that the chloride terms are reversed in the numerator and denominator compared to the cations, reflecting the opposite charge and flux direction of anions under the electrochemical gradient.[34] The derivation of the GHK voltage equation relies on the steady-state assumption that the net ionic current across the membrane is zero at rest, meaning the sum of individual ion currents (derived from the constant field flux equations) balances out.[35] This condition leads to an expression where V_m represents a permeability-weighted average of the individual Nernst equilibrium potentials for each ion, emphasizing the dominant role of the most permeable species (typically K⁺ at rest).[33] At physiological temperature (37°C), the prefactor \frac{RT}{F} approximates 26.7 mV, and converting the natural logarithm to base-10 yields a simplified form using 61.5 mV as the scaling factor for computational convenience: V_m = 61.5 \log_{10} \left( \frac{P_K [K^+]_{out} + P_{Na} [Na^+]_{out} + P_{Cl} [Cl^-]_{in}}{P_K [K^+]_{in} + P_{Na} [Na^+]_{in} + P_{Cl} [Cl^-]_{out}} \right) \ \text{(in mV)}. This approximation facilitates calculations while maintaining accuracy for mammalian systems.[36][37] In practical application to neuronal resting membrane potential, typical relative permeability ratios—such as P_{Na}/P_K \approx 0.05 and P_{Cl}/P_K \approx 0.45—combined with standard ion concentrations (e.g., [K⁺]ᵢ ≈ 140 mM, [K⁺]ₒ ≈ 5 mM; [Na⁺]ᵢ ≈ 15 mM, [Na⁺]ₒ ≈ 145 mM; [Cl⁻]ᵢ ≈ 7 mM, [Cl⁻]ₒ ≈ 110 mM) yield a V_m \approx -70 mV, closely matching experimental observations in many cell types.[33][1] The equation's key assumptions include a uniform (constant) electric field across the membrane thickness, independent movement of ions without interactions, and neglect of any electrogenic effects from active transport mechanisms like the sodium-potassium pump, focusing solely on passive permeability-driven fluxes.[34] These simplifications enable the GHK equation to serve as a foundational model for understanding multi-ion contributions to membrane potential, though real membranes may deviate under varying conditions.[35]Characteristics of Resting Potential
Calculation and Typical Magnitude
The resting membrane potential (RMP) in typical mammalian neurons is calculated using the Goldman-Hodgkin-Katz (GHK) voltage equation, which integrates the concentrations and relative permeabilities of major ions such as K⁺, Na⁺, and Cl⁻ across the membrane. Standard intracellular concentrations are approximately 140 mM for K⁺, 15 mM for Na⁺, and 7 mM for Cl⁻, while extracellular concentrations are about 5 mM for K⁺, 150 mM for Na⁺, and 120 mM for Cl⁻; relative permeabilities at rest are typically set with p_K = 1, p_Na = 0.05, and p_Cl = 0.45.[38] These parameters yield an RMP of approximately -70 mV, reflecting the dominant influence of K⁺ due to its high permeability and outward concentration gradient.[1] The primary contribution to this negativity comes from K⁺, with its Nernst equilibrium potential around -90 mV, which is partially offset by a small inward Na⁺ leak through low-permeability channels, pulling the potential toward the Na⁺ equilibrium of about +60 mV.[1] In steady-state conditions, the RMP represents the balance where net passive ion fluxes through leak channels equal the counteracting active transport by the Na⁺/K⁺-ATPase pump, maintaining ion gradients without net charge accumulation.[1] The magnitude of the RMP exhibits temperature dependence, often characterized by a Q₁₀ factor for underlying conductances and pump rates, which can shift the potential by several millivolts over physiological ranges (e.g., cooling typically hyperpolarizes due to reduced leak conductances).[39] Species variations also influence the value; for instance, the squid giant axon has an RMP of about -60 to -65 mV under standard conditions, attributable to differences in ion concentrations and channel properties.[40][15] Although often omitted in basic GHK calculations due to very low permeability at rest, Ca²⁺ can play a minor role in some cell types, where elevated extracellular Ca²⁺ concentrations may induce slight hyperpolarization by modulating surface charges or leak pathways.[41]Variations Across Cell Types
The resting membrane potential (RMP) exhibits considerable variation across cell types, shaped by differences in ion channel expression, permeability, and physiological demands. Excitable cells, such as neurons and muscle fibers, maintain a highly negative RMP to poise them for rapid depolarization during signaling, whereas non-excitable cells prioritize ion gradients for transport or homeostasis, resulting in less negative or more variable potentials. These adaptations ensure functional specialization, with potassium (K⁺) permeability often dominating in most cases to drive negativity, though contributions from other ions like sodium (Na⁺) or calcium (Ca²⁺) adjust the value accordingly.[1] In neurons, the RMP typically ranges from -60 to -80 mV, averaging around -70 mV, due to elevated K⁺ selectivity via inward-rectifier and leak channels that approximate the K⁺ equilibrium potential, enabling precise action potential initiation for neurotransmission.[1] Skeletal muscle fibers display a more hyperpolarized RMP of approximately -90 mV, supported by denser K⁺ channel density and active Na⁺/K⁺-ATPase activity, which sustains force generation during contraction.[42] Cardiac myocytes exhibit an RMP of -80 to -90 mV, where K⁺ conductance predominates but is modulated by the Na⁺/Ca²⁺ exchanger to influence automaticity and excitation-contraction coupling in the heart.[43][44] Non-excitable cells show greater diversity in RMP to support supportive or transport roles. Glial cells, including astrocytes, maintain an RMP near -80 mV through high K⁺ permeability, allowing them to buffer extracellular K⁺ and neurotransmitters for neuronal support.[45] Erythrocytes possess a weakly negative RMP of -10 to -15 mV owing to low ion permeability and anion dominance (e.g., Cl⁻), which minimizes energy expenditure while optimizing gas exchange.[46] Epithelial cells vary widely, often -40 to -60 mV, reflecting asymmetric ion transport for absorption or secretion across barriers like the intestine or kidney.[47] Smooth muscle cells have a less negative RMP of -50 to -60 mV, facilitated by balanced K⁺ and Ca²⁺ conductances, permitting graded depolarizations for sustained tone in vessels and viscera.[48] Even in non-animal systems, RMP adaptations highlight evolutionary conservation of membrane electrophysiology. Plant guard cells achieve a highly negative RMP of around -120 mV, powered by plasma membrane H⁺-ATPases and K⁺ channels, to drive turgor changes that regulate stomatal aperture for gas exchange and water conservation.[49]| Cell Type | Typical RMP (mV) | Brief Rationale |
|---|---|---|
| Neurons | -60 to -80 | High K⁺ selectivity via leak channels supports excitability for signal propagation.[1] |
| Skeletal muscle | -90 | Denser K⁺ channels maintain hyperpolarization for robust contraction readiness.[42] |
| Cardiac myocytes | -80 to -90 | K⁺ dominance modulated by Na⁺/Ca²⁺ exchanger enables rhythmic depolarization.[43] |
| Astrocytes (glial) | ~ -80 | K⁺ permeability buffers ions to aid neuronal homeostasis.[45] |
| Erythrocytes | -10 to -15 | Low permeability prioritizes anion flux for efficient O₂/CO₂ transport.[46] |
| Epithelial cells | -40 to -60 | Variable for directional ion/solute transport across tissues.[47] |
| Smooth muscle | -50 to -60 | Balanced conductances allow graded responses to stimuli.[48] |
| Plant guard cells | ~ -120 | H⁺-ATPase-driven negativity regulates stomatal turgor.[49] |