Differential voltage-dependent modulation of the ACh-gated K+ current by adenosine and acetylcholine

Inhibitory regulation of the heart is determined by both cholinergic M2 receptors (M2R) and adenosine A1 receptors (A1R) that activate the same signaling pathway, the ACh-gated inward rectifier K+ (KACh) channels via Gi/o proteins. Previously, we have shown that the agonist-specific voltage sensitivity of M2R underlies several voltage-dependent features of IKACh, including the ‘relaxation’ property, which is characterized by a gradual increase or decrease of the current when cardiomyocytes are stepped to hyperpolarized or depolarized voltages, respectively. However, it is unknown whether membrane potential also affects A1R and how this could impact IKACh. Upon recording whole-cell currents of guinea-pig cardiomyocytes, we found that stimulation of the A1R-Gi/o-IKACh pathway with adenosine only caused a very slight voltage dependence in concentration-response relationships (~1.2-fold EC50 increase with depolarization) that was not manifested in the relative affinity, as estimated by the current deactivation kinetics (τ = 4074 ± 214 ms at -100 mV and τ = 4331 ± 341 ms at +30 mV; P = 0.31). Moreover, IKACh did not exhibit relaxation. Contrarily, activation of the M2R-Gi/o-IKACh pathway with acetylcholine induced the typical relaxation of the current, which correlated with the clear voltage-dependent effect observed in the concentration-response curves (~2.8-fold EC50 increase with depolarization) and in the IKACh deactivation kinetics (τ = 1762 ± 119 ms at -100 mV and τ = 1503 ± 160 ms at +30 mV; P = 0.01). Our findings further substantiate the hypothesis of the agonist-specific voltage dependence of GPCRs and that the IKACh relaxation is consequence of this property.

Download Full-text

Voltage dependence of conductance changes evoked by glycine release in the zebrafish brain

Journal of Neurophysiology ◽

10.1152/jn.1995.73.6.2404 ◽

1995 ◽

Vol 73 (6) ◽

pp. 2404-2412 ◽

Cited By ~ 20

Author(s):

P. Legendre ◽

H. Korn

Keyword(s):

Voltage Dependence ◽

Reversal Potential ◽

Voltage Sensitivity ◽

M Cell ◽

Open Probability ◽

Similar Time ◽

Whole Cell ◽

Glycine Release ◽

Cell Recording ◽

Voltage Dependent

1. The kinetics and mechanisms underlying the voltage dependence of inhibitory postsynaptic currents (IPSCs) recorded in the Mauthner cell (M cell) were investigated in the isolated medulla of 52-h-old zebrafish larvae, with the use of whole cell and outside-out patch-clamp recordings. 2. Spontaneous miniature IPSCs (mIPSCs) were recorded in the presence of 10(-6) M tetrodotoxin (TTX), 10 mM MgCl2, and 0.1 mM [CaCl2]o. Depolarizing the cell from -50 to +50 mV did not evoke any significant change in the distribution of mIPSC amplitudes, whereas synaptic currents were prolonged at positive voltages. The average decay time constant was increased twofold at +50 mV. 3. The voltage dependence of the kinetics of glycine-activated channels was first investigated during whole cell recording experiments. Currents evoked by voltage steps in the presence of glycine (50 microM) were compared with those obtained without glycine. The increase in chloride conductance (gCl-) evoked by glycine was time and voltage dependent. Inactivation and reactivation of the chloride current were observed during voltage pulses from 0 to -50 mV and from -50 to 0 mV, respectively, and they occurred with similar time constants (2-3 s). During glycine application, voltage-ramp analysis revealed a shift in the reversal potential (ECl-) occurring at all [Cl-]i tested. 4. The basis of the voltage sensitivity of glycine-evoked gCl- was first analyzed by measuring the relative changes in the total open probability (NPo) of glycine-activated channels with voltage.(ABSTRACT TRUNCATED AT 250 WORDS)

Download Full-text

A time- and voltage-dependent K+ current in single cardiac cells from bullfrog atrium.

The Journal of General Physiology ◽

10.1085/jgp.88.6.777 ◽

1986 ◽

Vol 88 (6) ◽

pp. 777-798 ◽

Cited By ~ 27

Author(s):

J R Hume ◽

W Giles ◽

K Robinson ◽

E F Shibata ◽

R D Nathan ◽

...

Keyword(s):

Time Course ◽

Voltage Dependence ◽

Outward Current ◽

Cardiac Cells ◽

Delayed Rectifier ◽

Mechanical Dispersion ◽

Atrial Cells ◽

Voltage Dependent ◽

K Current ◽

Kinetics Of

Individual myocytes were isolated from bullfrog atrium by enzymatic and mechanical dispersion, and a one-microelectrode voltage clamp was used to record the slow outward K+ currents. In normal [K+]o (2.5 mM), the slow outward current tails reverse between -95 and -100 mV. This finding, and the observed 51-mV shift of Erev/10-fold change in [K+]o, strongly suggest that the "delayed rectifier" in bullfrog atrial cells is a K+ current. This current, IK, plays an important role in initiating repolarization, and it is distinct from the quasi-instantaneous, inwardly rectifying background current, IK. In atrial cells, IK does not exhibit inactivation, and very long depolarizing clamp steps (20 s) can be applied without producing extracellular K+ accumulation. The possibility of [K+]o accumulation contributing to these slow outward current changes was assessed by (a) comparing reversal potentials measured after short (2 s) and very long (15 s) activating prepulses, and (b) studying the kinetics of IK at various holding potentials and after systematically altering [K+]o. In the absence of [K+]o accumulation, the steady state activation curve (n infinity) and fully activated current-voltage (I-V) relation can be obtained directly. The threshold of the n infinity curve is near -50 mV, and it approaches a maximum at +20 mV; the half-activation point is approximately -16 mV. The fully activated I-V curve of IK is approximately linear in the range -40 to +30 mV. Semilog plots of the current tails show that each tail is a single-exponential function, which suggests that only one Hodgkin-Huxley conductance underlies this slow outward current. Quantitative analysis of the time course of onset of IK and of the corresponding envelope of tails demonstrate that the activation variable, n, must be raised to the second power to fit the sigmoid onset accurately. The voltage dependence of the kinetics of IK was studied by recording and curve-fitting activating and deactivating (tail) currents. The resulting 1/tau n curve is U-shaped and somewhat asymmetric; IK exhibits strong voltage dependence in the diastolic range of potentials. Changes in the [Ca2+]o in the superfusing Ringer's, and/or addition of La3+ to block the transmembrane Ca2+ current, show that the time course and magnitude of IK are not significantly modulated by transmembrane Ca2+ movements, i.e., by ICa. These experimentally measured voltage- and time-dependent descriptors of IK strongly suggest an important functional role for IK in atrial tissue: it initiates repolarization and can be an important determinant of rate-induced changes in action potential duration.

Download Full-text

Voltage-dependent block of cardiac inward-rectifying potassium current by monovalent cations.

The Journal of General Physiology ◽

10.1085/jgp.94.2.349 ◽

1989 ◽

Vol 94 (2) ◽

pp. 349-361 ◽

Cited By ~ 16

Author(s):

R D Harvey ◽

R E Ten Eick

Keyword(s):

Ventricular Myocytes ◽

Negative Slope ◽

Voltage Sensitivity ◽

Dependent Manner ◽

Inward Current ◽

Current Voltage ◽

Steady State Current ◽

Voltage Dependent ◽

Current Block ◽

K Current

The inward-rectifying K+ current (IK1) in cat ventricular myocytes, like inward-rectifying K+ currents in many other preparations, exhibited a negative slope conductance region at hyperpolarized membrane potentials that was time-dependent. This was evident as an inactivation of inward current elicited by hyperpolarizing voltage-clamp pulses resulting in a negative slope region of the steady-state current-voltage relationship at potentials negative to -140 mV. Removing extracellular Na+ prevented the development of the negative slope in this voltage region, suggesting that Na+ can block IK1 channels in a time- and voltage-dependent manner. The time and voltage dependence of Cs+-induced block of IK1 was also examined. Cs+ blocked inward current in a manner similar to that of Na+, but the former was much more potent. The fraction of current blocked by Cs+ in the presence of Na+ was reduced in a time- and voltage-dependent manner, which suggested that these blocking ions compete for a common or at least similar site of action. In the absence of Na+, inactivation of IK1 could also be induced by both Cs+ and Li+. However, Li+ was less potent than Na+ in this respect. Calculation of the voltage sensitivity of current block by each of these ions suggests that the mechanism of block by each is similar.

Download Full-text

Mechanism of Ba2+ block of M-like K channels of rod photoreceptors of tiger salamanders.

The Journal of General Physiology ◽

10.1085/jgp.103.1.45 ◽

1994 ◽

Vol 103 (1) ◽

pp. 45-66 ◽

Cited By ~ 20

Author(s):

L P Wollmuth

Keyword(s):

Time Course ◽

Voltage Dependence ◽

Cell Voltage ◽

Voltage Sensitivity ◽

Rod Photoreceptors ◽

Voltage Range ◽

Tiger Salamanders ◽

High K ◽

Voltage Dependent ◽

Time Courses

IKx is a voltage-dependent K+ current in the inner segment of rod photoreceptors that shows many similarities to M-current. The depression of IKx by external Ba2+ was studied with whole-cell voltage clamp. Ba2+ reduced the conductance and voltage sensitivity of IKx tail currents and shifted the voltage range over which they appeared to more positive potentials. These effects showed different sensitivities to Ba2+: conductance was the least sensitive (K0.5 = 7.6 mM), voltage dependence intermediate (K0.5 = 2.4 mM) and voltage sensitivity the most sensitive (K0.5 = 0.2 mM). Ca2+, Co2+, Mn2+, Sr2+, and Zn2+ did not have actions comparable to Ba2+ on the voltage dependence or the voltage sensitivity of IKx tail currents. In high K+ (100 mM), the voltage range of activation of IKx was shifted 20 mV negative, as was the tau-voltage relation. High K+ did not prevent the effect of Ba2+ on conductance, but abolished its ability to affect voltage dependence and voltage sensitivity. Ba2+ also altered the apparent time-course of activation and deactivation of IKx. Low Ba2+ (0.2 mM) slowed both deactivation and activation, with most effect on deactivation; at higher concentrations (1-25 mM), deactivation and activation time courses were equally affected, and at the highest concentrations, 5 and 25 mM Ba2+, the time course became faster than control. Rapid application of 5 mM Ba2+ suggested that the time dependent currents in Ba2+ reflect in part the slow voltage-dependent block and unblock of IKx channels by Ba2+. This blocking action of Ba2+ was steeply voltage-dependent with an apparent electrical distance of 1.07. Ba2+ appears to interact with IKx channels at multiple sites. A model which assumes that Ba2+ has a voltage-independent and a voltage-dependent blocking action on open or closed IKx channels reproduced many aspects of the data; the voltage-dependent component could account for both the Ba(2+)-induced shift in voltage dependence and reduction in voltage sensitivity of IKx tail currents.

Download Full-text

Mechanism of the Voltage Sensitivity of IRK1 Inward-rectifier K+ Channel Block by the Polyamine Spermine

The Journal of General Physiology ◽

10.1085/jgp.200409242 ◽

2005 ◽

Vol 125 (4) ◽

pp. 413-426 ◽

Cited By ~ 45

Author(s):

Hyeon-Gyu Shin ◽

Zhe Lu

Keyword(s):

Steady State ◽

Voltage Dependence ◽

Ion Selectivity ◽

Inward Rectifier ◽

Selectivity Filter ◽

K Channel ◽

Voltage Sensitivity ◽

Channel Block ◽

Head Groups ◽

Voltage Dependent

IRK1 (Kir2.1) inward-rectifier K+ channels exhibit exceedingly steep rectification, which reflects strong voltage dependence of channel block by intracellular cations such as the polyamine spermine. On the basis of studies of IRK1 block by various amine blockers, it was proposed that the observed voltage dependence (valence ∼5) of IRK1 block by spermine results primarily from K+ ions, not spermine itself, traversing the transmembrane electrical field that drops mostly across the narrow ion selectivity filter, as spermine and K+ ions displace one another during channel block and unblock. If indeed spermine itself only rarely penetrates deep into the ion selectivity filter, then a long blocker with head groups much wider than the selectivity filter should exhibit comparably strong voltage dependence. We confirm here that channel block by two molecules of comparable length, decane-bis-trimethylammonium (bis-QAC10) and spermine, exhibit practically identical overall voltage dependence even though the head groups of the former are much wider (∼6 Å) than the ion selectivity filter (∼3 Å). For both blockers, the overall equilibrium dissociation constant differs from the ratio of apparent rate constants of channel unblock and block. Also, although steady-state IRK1 block by both cations is strongly voltage dependent, their apparent channel-blocking rate constant exhibits minimal voltage dependence, which suggests that the pore becomes blocked as soon as the blocker encounters the innermost K+ ion. These findings strongly suggest the existence of at least two (potentially identifiable) sequentially related blocked states with increasing numbers of K+ ions displaced. Consequently, the steady-state voltage dependence of IRK1 block by spermine or bis-QAC10 should increase with membrane depolarization, a prediction indeed observed. Further kinetic analysis identifies two blocked states, and shows that most of the observed steady-state voltage dependence is associated with the transition between blocked states, consistent with the view that the mutual displacement of blocker and K+ ions must occur mainly as the blocker travels along the long inner pore.

Download Full-text

Properties of gap junction channels formed of connexin 45 endogenously expressed in human hepatoma (SKHep1) cells

AJP Cell Physiology ◽

10.1152/ajpcell.1995.268.2.c356 ◽

1995 ◽

Vol 268 (2) ◽

pp. C356-C365 ◽

Cited By ~ 104

Author(s):

A. P. Moreno ◽

J. G. Laing ◽

E. C. Beyer ◽

D. C. Spray

Keyword(s):

Gap Junction ◽

Voltage Dependence ◽

Hepatoma Cell ◽

Hepatoma Cell Line ◽

Voltage Sensitivity ◽

Gap Junction Channels ◽

Unitary Conductance ◽

Junction Protein ◽

Voltage Dependent ◽

Gap Junctional

We have evaluated the voltage dependence and unitary conductance of gap junctional channels that were recorded in a clone isolated from the hepatoma cell line SKHep1. In this clonal population (designated SKHep1A), Northern blots, immunoprecipitation, and immunohistochemical staining demonstrated the expression of connexin (Cx) 45; no other gap junction protein was identified by these techniques, although weak hybridization with Cx40 was detected. Macroscopic junctional conductance (gj) in these cells was low, averaging 1.3 nS, and was steeply voltage dependent. Parameters of voltage sensitivity were as follows: voltage at which voltage-sensitive conductance is reduced by 50%, 13.4 mV; steepness of relation, 0.115 (corresponding to 2.7 gating charges), and voltage-insensitive fraction of residual to total conductance approximately 0.06. Unitary conductance (gamma j) of these junctional channels averaged 32 +/- 8 pS; although gamma j was independent of transjunctional voltage (Vj), at high Vj values (> 50 mV), smaller conductance values were also detected. Open probabilities of the 30-pS channels at various Vj values closely matched the predicted voltage-dependent component of macroscopic gj, the residual conductance at high Vj might be attributable to the smaller conductance events. The voltage dependence of human Cx45 gap junction channels is as steep as that seen for channels formed by Xenopus Cx38 and is much steeper than that previously reported for channels formed of the highly homologous chick Cx45 and for other mammalian connexins expressed either endogenously or exogenously.

Download Full-text

Intrinsic versus extrinsic voltage sensitivity of blocker interaction with an ion channel pore

The Journal of General Physiology ◽

10.1085/jgp.200910324 ◽

2010 ◽

Vol 135 (2) ◽

pp. 149-167 ◽

Cited By ~ 7

Author(s):

Juan Ramón Martínez-François ◽

Zhe Lu

Keyword(s):

Electric Field ◽

Voltage Dependence ◽

Ion Selectivity ◽

Systematic Investigation ◽

Selectivity Filter ◽

Voltage Sensitivity ◽

Channel Block ◽

Boltzmann Function ◽

Voltage Dependent ◽

Gated Channel

Many physiological and synthetic agents act by occluding the ion conduction pore of ion channels. A hallmark of charged blockers is that their apparent affinity for the pore usually varies with membrane voltage. Two models have been proposed to explain this voltage sensitivity. One model assumes that the charged blocker itself directly senses the transmembrane electric field, i.e., that blocker binding is intrinsically voltage dependent. In the alternative model, the blocker does not directly interact with the electric field; instead, blocker binding acquires voltage dependence solely through the concurrent movement of permeant ions across the field. This latter model may better explain voltage dependence of channel block by large organic compounds that are too bulky to fit into the narrow (usually ion-selective) part of the pore where the electric field is steep. To date, no systematic investigation has been performed to distinguish between these voltage-dependent mechanisms of channel block. The most fundamental characteristic of the extrinsic mechanism, i.e., that block can be rendered voltage independent, remains to be established and formally analyzed for the case of organic blockers. Here, we observe that the voltage dependence of block of a cyclic nucleotide–gated channel by a series of intracellular quaternary ammonium blockers, which are too bulky to traverse the narrow ion selectivity filter, gradually vanishes with extreme depolarization, a predicted feature of the extrinsic voltage dependence model. In contrast, the voltage dependence of block by an amine blocker, which has a smaller “diameter” and can therefore penetrate into the selectivity filter, follows a Boltzmann function, a predicted feature of the intrinsic voltage dependence model. Additionally, a blocker generates (at least) two blocked states, which, if related serially, may preclude meaningful application of a commonly used approach for investigating channel gating, namely, inferring the properties of the activation gate from the kinetics of channel block.

Download Full-text

Phe-Met-Arg-Phe-amide Activates a Novel Voltage-dependent K+ Current through a Lipoxygenase Pathway in Molluscan Neurones

The Journal of General Physiology ◽

10.1085/jgp.110.5.611 ◽

1997 ◽

Vol 110 (5) ◽

pp. 611-628 ◽

Cited By ~ 14

Author(s):

K.S. Kits ◽

J.C. Lodder ◽

M.J. Veerman

Keyword(s):

Arachidonic Acid ◽

G Protein ◽

Lymnaea Stagnalis ◽

Reversal Potential ◽

Outward Current ◽

Egg Laying ◽

Voltage Sensitivity ◽

Lipoxygenase Pathway ◽

Voltage Dependent ◽

K Current

The neuropeptide Phe-Met-Arg-Phe-amide (FMRFa) dose dependently (ED50 = 23 nM) activated a K+ current in the peptidergic caudodorsal neurones that regulate egg laying in the mollusc Lymnaea stagnalis. Under standard conditions ([K+]o = 1.7 mM), only outward current responses occurred. In high K+ salines ([K+]o = 20 or 57 mM), current reversal occurred close to the theoretical reversal potential for K+. In both salines, no responses were measured below −120 mV. Between −120 mV and the K+ reversal potential, currents were inward with maximal amplitudes at ∼−60 mV. Thus, U-shaped current–voltage relations were obtained, implying that the response is voltage dependent. The conductance depended both on membrane potential and extracellular K+ concentration. The voltage sensitivity was characterized by an e-fold change in conductance per ∼14 mV at all [K+]o. Since this result was also obtained in nearly symmetrical K+ conditions, it is concluded that channel gating is voltage dependent. In addition, outward rectification occurs in asymmetric K+ concentrations. Onset kinetics of the response were slow (rise time ∼650 ms at −40 mV). However, when FMRFa was applied while holding the cell at −120 mV, to prevent activation of the current but allow activation of the signal transduction pathway, a subsequent step to −40 mV revealed a much more rapid current onset. Thus, onset kinetics are largely determined by steps preceding channel activation. With FMRFa applied at −120 mV, the time constant of activation during the subsequent test pulse decreased from ∼36 ms at −60 mV to ∼13 ms at −30 mV, confirming that channel opening is voltage dependent. The current inactivated voltage dependently. The rate and degree of inactivation progressively increased from −120 to −50 mV. The current is blocked by internal tetraethylammonium and by bath- applied 4-aminopyridine, tetraethylammonium, Ba2+, and, partially, Cd2+ and Cs+. The response to FMRFa was affected by intracellular GTPγS. The response was inhibited by blockers of phospholipase A2 and lipoxygenases, but not by a cyclo-oxygenase blocker. Bath-applied arachidonic acid induced a slow outward current and occluded the response to FMRFa. These results suggest that the FMRFa receptor couples via a G-protein to the lipoxygenase pathway of arachidonic acid metabolism. The biophysical and pharmacological properties of this transmitter operated, but voltage-dependent K+ current distinguish it from other receptor-driven K+ currents such as the S-current- and G-protein-dependent inward rectifiers.

Download Full-text

Nonsensing residues in S3–S4 linker’s C terminus affect the voltage sensor set point in K+ channels

The Journal of General Physiology ◽

10.1085/jgp.201711882 ◽

2018 ◽

Vol 150 (2) ◽

pp. 307-321 ◽

Cited By ~ 7

Author(s):

Joao L. Carvalho-de-Souza ◽

Francisco Bezanilla

Keyword(s):

Intermediate State ◽

Voltage Dependence ◽

State Model ◽

Voltage Sensitivity ◽

Voltage Sensing ◽

K Channels ◽

C Terminus ◽

Voltage Dependent ◽

Arginine Residues ◽

Three State Model

Voltage sensitivity in ion channels is a function of highly conserved arginine residues in their voltage-sensing domains (VSDs), but this conservation does not explain the diversity in voltage dependence among different K+ channels. Here we study the non–voltage-sensing residues 353 to 361 in Shaker K+ channels and find that residues 358 and 361 strongly modulate the voltage dependence of the channel. We mutate these two residues into all possible remaining amino acids (AAs) and obtain Q-V and G-V curves. We introduced the nonconducting W434F mutation to record sensing currents in all mutants except L361R, which requires K+ depletion because it is affected by W434F. By fitting Q-Vs with a sequential three-state model for two voltage dependence–related parameters (V0, the voltage-dependent transition from the resting to intermediate state and V1, from the latter to the active state) and G-Vs with a two-state model for the voltage dependence of the pore domain parameter (V1/2), Spearman’s coefficients denoting variable relationships with hydrophobicity, available area, length, width, and volume of the AAs in 358 and 361 positions could be calculated. We find that mutations in residue 358 shift Q-Vs and G-Vs along the voltage axis by affecting V0, V1, and V1/2 according to the hydrophobicity of the AA. Mutations in residue 361 also shift both curves, but V0 is affected by the hydrophobicity of the AA in position 361, whereas V1 and V1/2 are affected by size-related AA indices. Small-to-tiny AAs have opposite effects on V1 and V1/2 in position 358 compared with 361. We hypothesize possible coordination points in the protein that residues 358 and 361 would temporarily and differently interact with in an intermediate state of VSD activation. Our data contribute to the accumulating knowledge of voltage-dependent ion channel activation by adding functional information about the effects of so-called non–voltage-sensing residues on VSD dynamics.

Download Full-text

Major contribution of sarcoplasmic reticulum Ca2+ depletion during long-lasting activation of skeletal muscle

The Journal of General Physiology ◽

10.1085/jgp.201310957 ◽

2013 ◽

Vol 141 (5) ◽

pp. 557-565 ◽

Cited By ~ 10

Author(s):

Gaëlle Robin ◽

Bruno Allard

Keyword(s):

Skeletal Muscle ◽

Sarcoplasmic Reticulum ◽

Voltage Dependence ◽

Muscle Fibers ◽

Voltage Sensitivity ◽

Mouse Muscle ◽

Physiological Conditions ◽

Relative Contribution ◽

Voltage Dependent ◽

Steady State Inactivation

Depolarization of skeletal muscle fibers induces sarcoplasmic reticulum (SR) Ca2+ release and contraction that progressively decline while depolarization is maintained. Voltage-dependent inactivation of SR Ca2+ release channels and SR Ca2+ depletion are the two processes proposed to explain the decline of SR Ca2+ release during long-lasting depolarizations. However, the relative contribution of these processes, especially under physiological conditions of activation, is not clearly established. Using Fura-2 and Fluo-5N to monitor cytosolic and SR Ca2+ changes, respectively, in voltage-controlled mouse muscle fibers, we show that 2-min conditioning depolarizations reduce voltage-activated cytosolic Ca2+ signals with a V1/2 of −53 mV but also induce SR Ca2+ depletion that decreased the releasable pool of Ca2+ with the same voltage sensitivity. In contrast, measurement of SR Ca2+ changes indicated that SR Ca2+ release channels were inactivated after SR had been depleted and in response to much higher depolarizations with a V1/2 of −13 mV. In response to trains of action potentials, cytosolic Ca2+ signals decayed with time, whereas SR Ca2+ changes remained stable over 1-min stimulation, demonstrating that SR Ca2+ depletion is exclusively responsible for the decline of SR Ca2+ release under physiological conditions of excitation. These results suggest that previous studies using steady-state inactivation protocols to investigate the voltage dependence of Ca2+ release inactivation in fact probed the voltage dependence of SR Ca2+ depletion, and that SR Ca2+ depletion is the only process that leads to Ca2+ release decline during continuous stimulation of skeletal muscle.

Download Full-text