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This summary article presents an overview of the molecular relationships among the voltage-gated potassium channels and a standard nomenclature for them, which is derived from the IUPHAR Compendium of Voltage-Gated Ion Channels. The complete Compendium, including data tables for each member of the potassium channel family can be found at http://www.iuphar-db.org/iuphar-ic/.
We have characterized the membrane currents in the H9c2 clonal muscle cell line derived from embryonic rat ventricle. These cells, established by selective serial passage and clonal proliferation, have been found by Hescheler and coworkers to express dihydropyridine-sensitive calcium channels that respond to beta-adrenergic stimulation. We have investigated the macroscopic and elementary currents in these cells by using standard patch-clamp methods. In cells that are kept confluent for 3-4 weeks, we have confirmed the expression of L-type calcium channels and additionally establish that the unitary conductance of many, but not all, of these channels (25 pS in 70 mM barium) is equal to that of cardiac rather than skeletal muscle. When the cells are proliferating rapidly, calcium channels are sparse or absent, but at least two distinct potassium channels and a nonspecific cation channel are observed. The nonspecific channel exhibits a conductance of 30 pS in physiological saline and conducts sodium, potassium, and calcium with nearly equal efficacy. Several unusual properties distinguish this nonspecific channel from others described previously. Gating is voltage dependent, with slow activation and marked increases in open probability at positive potentials. Unlike voltage, activation and marked increases in open probability at positive potentials. Unlike voltage, changes in [Ca2+] or in membrane stretch do not noticeably influence activity. In conclusion, our work and that of Hescheler et al indicate that H9c2 cells are potentially valuable surrogates for the investigation of ion channel regulation and muscular gene expression.
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Resistance arteries exist in a maintained contracted state from which they can dilate or constrict depending on need. In many cases, these arteries constrict to membrane depolarization and dilate to membrane hyperpolarization and Ca-channel blockers. We discuss recent information on the regulation of arterial smooth muscle voltage-dependent Ca channels by membrane potential and vasoconstrictors and on the regulation of membrane potential and K channels by vasodilators. We show that voltage-dependent Ca channels in the steady state can be open and very sensitive to membrane potential changes in a range that occurs in resistance arteries with tone. Many synthetic and endogenous vasodilators act, at least in part, through membrane hyperpolarization caused by opening K channels. We discuss evidence that these vasodilators act on a common target, the ATP-sensitive K (KATP) channel that is inhibited by sulfonylurea drugs. We propose the following hypotheses that presently explain these findings: 1) arterial smooth muscle tone is regulated by membrane potential primarily through the voltage dependence of Ca channels; 2) many vasoconstrictors act, in part, by opening voltage-dependent Ca channels through membrane depolarization and activation by second messengers; and 3) many vasodilators work, in part, through membrane hyperpolarization caused by KATP channel activation.
The membrane potential (Um), the main factor of the excitation-contraction coupling, of human allantochorial placental vascular smooth muscle cells (VSMCs) has been previously shown to depend on voltage-sensitive K+ channels. These channels were blocked by high external K+. To characterize other channels which regulated Um, various constrictor or/and vasodilators and channel blockers were used. Serotonin depolarized VSMCs, in normal medium, but induced a more marked depolarization in VSMCs predepolarized by high external K+. This depolarization was inhibited by nifedipine, a blocker of voltage-gated Ca2+ channels. Acetylcholine, sodium nitroprusside (without effect on Um in normal medium), hyperpolarized the predepolarized-high K+ medium VSMCs. This hyperpolarization was inhibited after addition of charybotoxin (a blocker of Ca2+-activated K+ channels) or/and glibenclamide (a blocker of ATP-sensitive K+ channels). A similar effect was obtained with isoproterenol. These results indicated that membrane potential of human placental allantochorial VSMCs was regulated by voltage-gated, Ca2+- and ATP-sensitive K+ channels and by voltage-dependent Ca2+ channels.
Potassium channels play an important role in a variety of transport operations in renal tubules. Considerable progress has been made in the analysis of their location and regulation by applying patch clamp techniques to native and cloned renal potassium channels. Potassium channels serve several functions, including the generation of the cell-negative potential and regulation of cell volume, particularly in the defense against cell swelling; they are also important for recycling and secretion of potassium. This review focuses on the properties of several potassium channels in the kidney and the important role in the regulation of potassium secretion in the distal nephron.
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Potassium channels catalyze the selective transfer of potassium across the cell membrane and are essential for setting the resting potential in cells, controlling heart rate and modulating the firing pattern in neurons. Tetraethylammonium (TEA) blocks ion conduction through potassium channels in a voltage-dependent manner from both sides of the membrane. Here we show the structural basis of TEA blockade by cocrystallizing the prokaryotic potassium channel KcsA with two selective TEA analogs. TEA binding at both sites alters ion occupancy in the selectivity filter; these findings underlie the mutual destabilization and voltage-dependence of TEA blockade. We propose that TEA blocks potassium channels by acting as a potassium analog at the dehydration transition step during permeation.
Potassium channels are transmembrane proteins that allow this ion to diffuse through the plasma membrane. By participating in the generation of membrane potential they regulate intracellular calcium levels and vascular smooth muscle contraction. Voltage-gated and ATP-gated potassium channels have been described in vessel smooth muscle. Minoxidil and diazoxide vasodilate by opening ATP-gated potassium channels. Soon other K-ATP channel openers will be available. It has been suggested that hypoxic vasodilatation and shock are due to excessive activation of potassium channels. Mutations in potassium channels have been implied in the pathogenesis of essential hypertension.
Potassium currents play a critical role in action potential repolarization, setting of the resting membrane potential, control of neuronal firing rates, and regulation of neurotransmitter release. The diversity of the potassium channels that generate these currents is nothing less than staggering. This diversity is generated by multiple genes (as many as 100 and perhaps more in some creatures) encoding the pore-forming channel alpha subunits, alternative splicing of channel gene transcripts, formation of heteromultimeric channels, participation of auxiliary (non-pore-forming) beta and other subunits, and modulation of channel properties by post-translational modifications and other mechanisms. Prominent among the potassium channels are several families of calcium activated potassium channels, which are highly selective for potassium ions as their charge carrier, and require intracellular calcium for channel gating. The modulation of one of these families, that of the large conductance calcium activated and voltage-dependent potassium channels, has been especially widely studied. In this review we discuss a few selected examples of the modulation of these channels, to illustrate some of the molecular mechanisms and physiological consequences of ion channel modulation.
Potassium channels are membrane proteins that allow the passive diffusion of potassium down its electrochemical gradient. They play a critical role in many cellular processes and have, therefore, been extensively studied. Over the past several years, the molecular structures of several types of potassium channels have been elucidated. This review investigates the most recent findings regarding the structure, regulation and pathophysiology of potassium channels.
Potassium channels are an important determinant of smooth muscle excitability and force generation. Two potassium channels have been fully described in airway smooth muscle: large conductance, calcium-activated potassium channels and voltage-dependent delayed rectifier channels. This article will review the biophysics and pharmacology of these channels and discuss what is currently known with respect to their regulation and physiological significance.
OBJECTIVE: To study the expressions of L-type calcium channel alpha1c and potassium channel Kv4.3 at early stages of atrial fibrillation in a rapid paced primary cultured atrial myocyte model. METHODS: Primary rat atrial myocytes were cultured and a rapid paced cell model was established. The atrial cells were divided into five groups with pacing durations within 0 and 24 h. Reverse transcription-polymerase chain reaction and Western blot were applied to detect the messenger ribonucleic acid (mRNA) and proteins of L-type calcium channel alpha1c and potassium channel Kv4.3, respectively. RESULTS: mRNA expression of L-type calcium channel alpha1c reduced after 6 h of rapid pacing and continued to decline as the pacing process. The decrease of L-type calcium channel alpha1c protein was paralleled with mRNA expression and reached the lowest levels at 24 h. Similarly, changes of potassium channel Kv4.3 protein and mRNA were paralleled. Kv4.3 mRNA was not altered within the first 6 h. It was reduced after 12 h. However, longer pacing periods did not further decrease mRNA and protein expression levels of potassium channel Kv4.3. CONCLUSIONS: Expressions of L-type calcium channel alpha1c and potassium channel Kv4.3 were both reduced at different levels in early phase of rapid pacing atrial myocytes. It implicates the occurrence of ion channel remodeling of atrial myocytes, which may serve as molecular mechanism of electrical remodeling in the development of atrial fibrillation.
Potassium channels in the apical and basolateral membranes of tubule cells serve several important functions. They contribute to the generation of the cell-negative potential, mediate volume reductions following cell swelling and play a key role in secretion of potassium in both the thick ascending limb of Henle's loop and principal tubule cells of the initial and cortical collecting tubules. Secretion of potassium occurs via a well-defined class of potassium channels distinguished by their low single channel conductance, mild inward rectification, high sensitivity to inhibition by low pH, millimolar concentrations of ATP, arachidonic acid and PKC, and stimulation by vasopressin and pretreatment with a high potassium diet. Genes encoding several isoforms of this channel have been cloned and the proteins located to the apical membranes of cells lining the thick ascending limb of Henle's loop and the collecting tubules, and progress made concerning their structure-function relationship.
Potassium channels, a group of specialized membrane proteins, enable K+ ions to flow selectively across cell membranes. Transmembrane K+ currents underlie electrical signalling in neurons and other excitable cells. The atomic structure of a bacterial K+ channel pore has been solved by means of X-ray crystallography. To the extent that the prokaryotic pore is representative of other K+ channels, this landmark achievement has profound implications for our general understanding of K+ channels. But serious doubts have been raised concerning whether the prokaryotic K+ channel pore does actually represent those of eukaryotes. Here we have addressed this fundamental issue by substituting the prokaryotic pore into eukaryotic voltage-gated and inward-rectifier K+ channels. The resulting chimaeras retain the respective functional hallmarks of the eukaryotic channels, which indicates that the ion conduction pore is indeed conserved among K+ channels.
Potassium channels are tetrameric membrane-spanning proteins that provide a selective pore for the conduction of K(+) across the cell membranes. One of the main physiological functions of potassium channels is efficient and very selective transport of K(+) ions through the membrane to the cell. Classical views of ion selectivity are summarized within a historical perspective, and contrasted with the molecular dynamics (MD) simulations free energy perturbation (FEP) performed on the basis of the crystallographic structure of the KcsA phospholipid membrane. The results show that the KcsA channel does not select for K(+) ions by providing a binding site of an appropriate (fixed) cavity size. Rather, selectivity for K(+) arises directly from the intrinsic local physical properties of the ligands coordinating the cation in the binding site, and is a robust feature of a pore symmetrically lined by backbone carbonyl groups. Further analysis reveals that it is the interplay between the attractive ion-ligand (favoring smaller cation) and repulsive ligand-ligand interactions (favoring larger cations) that is the basic element governing Na(+)/K(+) selectivity in flexible protein binding sites. Because the number and the type of ligands coordinating an ion directly modulate such local interactions, this provides a potent molecular mechanism to achieve and maintain a high selectivity in protein binding sites despite a significant conformational flexibility.
Potassium channels are integral membrane proteins that play a crucial role in regulating diverse cell functions in both electrically excitable and non-excitable cells. Molecular cloning has revealed a diverse family of genes that encode these proteins, and a variety of experimental strategies have defined functional domains. We have cloned, over-expressed and purified the KcsA potassium channel to homogeneity and reconstituted this channel protein with phospholipids to form two-dimensional crystals. The crystals belong to plane group p4 and have unit cell dimensions of a=b=48 A. A projection map at 6 A resolution has been obtained by electron crystallography. The map shows that the protein is a homotetramer, having a low-density region on the 4-fold axis that is the site of the ion conduction pathway. Each monomer contains density features that are consistent with the molecular model of a truncated form of KcsA recently determined by X-ray crystallography.
Potassium channels that are inhibited by internal ATP (K(ATP) channels) provide a critical link between metabolism and cellular excitability. Protein kinase C (PKC) acts on K(ATP) channels to regulate diverse cellular processes, including cardioprotection by ischemic preconditioning and pancreatic insulin secretion. PKC action decreases the Hill coefficient of ATP binding to cardiac K(ATP) channels, thereby increasing their open probability at physiological ATP concentrations. We show that PKC similarly regulates recombinant channels from both the pancreas and heart. Surprisingly, PKC acts via phosphorylation of a specific, conserved threonine residue (T180) in the pore-forming subunit (Kir6.2). Additional PKC consensus sites exist on both Kir and the larger sulfonylurea receptor (SUR) subunits. Nonetheless, T180 controls changes in open probability induced by direct PKC action either in the absence of, or in complex with, the accessory SUR1 (pancreatic) or SUR2A (cardiac) subunits. The high degree of conservation of this site among different K(ATP) channel isoforms suggests that this pathway may have wide significance for the physiological regulation of K(ATP) channels in various tissues and organelles.