Activation K+channels

Cardiac IKi is the major K+ current responsible for stabilizing the resting membranepotential and shaping the late phase of repolarization of the action potential in cardiac myocytes. The name should not be confused with that of an Intermediate conductance calcium-activated K+ channel, which sometimes is also called IK1. 

This subfamily including the large- (BKCa), intermediate-(IKca), and small-conductance (SKCa) Ca2+-activated K + channels are activated by increases in intracellular free Ca2+ concentration. The opening of DCca and SKCa channels are less voltage-dependent, whereas the activation of BKCa channel has steep voltage sensitivity. 

First, their opening during somato-dendritic action potentials provides the source of the increased intracellular [Ca +] required to open Ca +-activated K+ channels — BK channels, to accelerate spike repolarisation, and SK channels, to induce spike-train adaptation and limit repetitive firing. The BK channels are activated (primarily) following entry of Ca + through L-type channels the source of Ca + for SK channel activation varies with different neurons, and may be either through L-type or N-type channels. 

Chen Y, Yu L. Differential regulation by cAM P-dependent protein kinase and protein kinase C of the k opioid receptor coupling to a G protein-activated K+ channel. J Biol Chem 1994 269 7839-7842. 

Membrane depolarization typically results from an increase in Na+ conductance. In addition, mobilization of intracellular Ca2+ from the endoplasmic or sarcoplasmic reticulum and the influx of extracellular Ca2+ appear to be elicited by ACh acting on muscarinic receptors (see Ch. 22). The resulting increase in intracellular free Ca2+ is involved in activation of contractile, metabolic and secretory events. Stimulation of muscarinic receptors has been linked to changes in cyclic nucleotide concentrations. Reductions in cAMP concentrations and increases in cGMP concentrations are typical responses (see Ch. 21). These cyclic nucleotides may facilitate contraction or relaxation, depending on the particular tissue. Inhibitory responses also are associated with membrane hyperpolarization, and this is a consequence of an increased K+ conductance. Increases in K+ conductance may be mediated by a direct receptor linkage to a K+ channel or by increases in intracellular Ca2+, which in turn activate K+ channels. Mechanisms by which muscarinic receptors couple to multiple cellular responses are considered later. 

From the earliest measurements of tissue calcium, it was clear that total calcium is largely a measure of stored calcium. Through the years, scientists have used a variety of indirect measures of [Ca2+]j. These include shortening of or tension in muscles secretion from secretory cells the activity of Ca2+-dependent enzymes, most notably glycogen phosphorylase and flux of K+, or K+ currents, as a reflection of Ca2+-activated K+ channels. In addition, investigators often use the radioactive calcium ion [45Ca2+] as an indirect indicator of Ca2+ concentrations and Ca2+ movements. 

Recent work using confocal microscopy has found localized increases of [Ca2+]j named Ca2+ sparks which are due to the release of Ca2+ from one or a small number of RyRs (Jaggar et al 2000). These localized releases of Ca2+ activate Ca2+-dependent channels in the surface membrane (Perez et al 2001). Activation of the Ca2+-activated K+ current will hyperpolarize the membrane potential (Herrera et al 2001) and thereby decrease Ca2+ entry into the cell on voltage-dependent Ca2+ channels. This provides a mechanism whereby Ca2+ release from the SR can decrease contraction. It is therefore important, in different smooth muscles, to consider to what extent SR Ca2+ release activates rather than decreases contraction. It is, of course, possible that, in the same smooth muscle, SR release may sometimes directly activate contraction and, at other times, decrease it by activating K+ channels. 

STOCs arise from the concerted activation of up to 100 Ca2+-activated K+ channels (KCa) in the sarcolemma as a consequence of Ca2+ release from the SR. This release may take the form either of non-propagating focal events such as sparks or puffs , or of more regenerative Ca2+ waves. Since a temporal correlation between them exists, STOCs have been attributed to focal nonpropagating Ca2+ release events. However, this view requires that each STOC is a spatially restricted membrane current that occurs at selected areas of membrane closely apposed to the SR. While essential to the prevalent hypothesis for STOCs,... 

Young We have data showing that induction of a Ca2+ wave in cultured myometrial cells that lack L-type Ca2+ channels causes activation of Ca2+-activated K+ channels that we think are store-operated. This is just with passage of a Ca2+ wave without thapsigargin. 

Transient spontaneous increases in intracellular ionized Ca2+ concentration, [Ca2+] , were first detected in smooth muscle as bursts of openings of Ca2+ activated K+ channels (Benham Bolton 1986). Several years later, laser scanning confocal imaging showed that similar spontaneous transient increases in... 

During the action potential in vas deferens or urinary bladder the rise in [Ca2+] close under the cell membrane is responsible, in combination with the depolarization, for the repolarization phase as it causes the opening of Ca2+-activated K+ channels through which a large repolarizing outward current flows (Arnaudeau et al 1997, Imaizumi et al 1998, Ohi et al 2001). This may lead to a transient period of hyperpolarization (an afterhyperpolarization ) following the action potential (Imaizumi et al 1998). 

ZhuGe R, Fogarty KE, Tuft RA, Lifshitz LM, Sayar K, Walsh JV 2000 Dynamics of signaling between Ca2+ sparks and Ca2+-activated K+ channels studied with a novel image-based method for direct intracellular measurement of ryanodine receptor Ca2+ current. J Gen... 

Cox DH, Aid rich RW 2000 Role of the /) 1 subunit in large-conductance Ca2+-activated K+ channel gating energetics mechanisms of enhanced Ca2+ sensitivity. J Gen Physiol 116 411-432... 

Cox DH, Cui J, Aldrich RW 1997 Allosteric gating of a large conductance Ca-activated K+ channel. J Gen Physiol 110 257—281... 

Creed KE, Ishikawa S, Ito Y 1983 Electrical and mechanical activity recorded from rabbit urinary bladder in response to nerve stimulation. J Physiol 338 149-164 Cui J, Cox DH, Aldrich RW 1997 Intrinsic voltage dependence and Ca2+ regulation of mslo large conductance Ca-activated K+ channels. J Gen Physiol 109 647-673 Fabiato A 1983 Calcium-induced release of calcium from the cardiac sarcoplasmic reticulum. Am J Physiol 245 0-04... 

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