Channel potassium

K channels selectively transport K across membranes, hyperpolarise cells, set membrane potentials, and control the duration of action potentials, among a myriad of other functions. They use diverse forms of gating, but they all have very similar ion permeabilities. All K channels show a selectivity sequence of Rb Cs, whereas the transport of the smallest alkali metal ions Na and Li+ is very slow — typically the permeability for K+ is at least 10 that of Na . The determination of the X-ray structure of the K+ ion channel has allowed us to understand how it selectively filters completely dehydrated K+ ions, but not the smaller Na+ ions. Not only does this molecular filter select the ions to be transported, but also the electrostatic repulsion between K+ ions, which pass through this molecular filter in Indian file, provides the force to drive the ions rapidly through the channel at a rate of lO —10 per second (reviewed in Doyle et al., 1998 MacKinnon, 2004).  

The 2003 Nobel prize for chemistry was awarded to Rod MacKinnon for his pioneering work in this area. 

These mutant fruit flies shake violently when anaesthetised with ether. 

FIGURE 9.3 One of the first pictures of a tetrameric K channel with a selectivity filter made of pore loops. A linear representation of a Shaker K channel subunit on top shows shaded hydrophobic segments SI—S6 and a region designated the pore loop. A partial amino acid sequence from the Shaker K channel pore loop highlights amino acids shown to interact with extracellular scorpion toxins ( ), intracellular tetraethylammonium (f), and ions (+). The pore loop was proposed to reach into the membrane (middle) and form a selectivity filter at the centre of four subunits (bottom). (From MacKinnon, 2004. Reproduced with permission from John Wiley Sons.) 

FIGURE 9.4 (a) A ribbon representation of the KcsA K channel with its four subunits coloured differently. The channel is oriented with the 

Potassium channels occur in the plasma membrane of a variety of different cell types throughout the body. 

K channels are associated with the recovery or repolarization of excitable cells after depolarization. In general, they function to inhibit excitatory processes. As mentioned before, ASM exhibits only a low level of electrical excitability without the development of action potentials. Instead, ASM displays slow wave activity thought to represent action potentials which are suppressed by the opening of K channels, with the efflux of from the cell rectifying any tendency to depolarization (Small atU., 1993). Thus, ASM is strongly rectified (i.e. more resistant to depolarization than to hyperpolarization). 

These findings have heightened interest in the role of channels in ASM since it is recognized that imder conditions of channel blockade, where the ASM cell has lost its ability to rectify, ASM excitability is increased and generation of action potentials is possible experimentally. This excitability is analogous to some of the elec-trophysiological changes recorded in ASM obtained from asthmatic airways (Akasaka aal., 1975). 

The subtype of K channel responsible for determining the outwardly rectifying behaviour remains to be identified - possible candidates include the lai conductance Ca -dependent K channel (BKca), and the delayed rectifier channel (K Fleischmann etal., 1994). 

The opening of K channels has been implicated as one of the mechanisms by which raised cytosolic cAMP relaxes ASM. Using the patch clamp technique for 

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There ate many classes of anticonvulsant agent in use, many associated with side effect HabiUties of unknown etiology. Despite many years of clinical use, the mechanism of action of many anticonvulsant dmgs, with the exception of the BZs, remains unclear and may reflect multiple effects on different systems, the summation of which results in the anticonvulsant activity. The pharmacophore stmctures involved are diverse and as of this writing there is htde evidence for a common mechanism of action. Some consensus is evolving, however, in regard to effects on sodium and potassium channels (16) to reduce CNS excitation owing to convulsive episodes. 

The anainoacridines, tacrine (19) and its 1-hydroxy metaboUte, velnacrine (20), are reversible inhibitors of AChE. Tacrine was synthesi2ed in the 1940s and has been used clinically for the treatment of myasthenia gravis and tardive dyskinesia (115). Placebo-controUed studies have indicated modest efficacy of tacrine to treat AD dementia (122,123) and in 1993 the dmg was recommended for approval by the PDA under the trade name Cognex. Tacrine (19) has been shown to interact with sites other than AChE, such as potassium channels (124) and muscarinic receptors. However, these interactions are comparatively weak and are not thought to contribute to the biological activity of the dmg at therapeutic levels (115). 

An alternative approach to stimulate cholinergic function is to enhance the release of acetylcholine (ACh). Compounds such as the aminopyridines increase the release of neurotransmitters (148). The mechanism by which these compounds modulate the release of acetylcholine is likely the blockade of potassium channels. However, these agents increase both basal (release in the absence of a stimulus) and stimulus-evoked release (148). 4-Aminopyridine [504-24-5] was evaluated in a pilot study for its effects in AD and found to be mildly effective (149). 

Opiates iateract with three principal classes of opioid GPCRs )J.-selective for the endorphiQS,5-selective for enkephalins, and K-selective for dynorphias (51). AU. three receptors have been cloned. Each inhibits adenylate cyclase, can activate potassium channels, and inhibit A/-type calcium channels. The classical opiates, morphine and its antagonists naloxone (144) and naltrexone (145), have moderate selectivity for the. -receptor. Pharmacological evidence suggests that there are two subtypes of the. -receptor and three subtypes each of the 5- and K-receptor. An s-opiate receptor may also exist. 

Cromakalim (137) is a potassium channel activator commonly used as an antihypertensive agent (107). The rationale for the design of cromakalim is based on P-blockers such as propranolol (115) and atenolol (123). Conformational restriction of the propanolamine side chain as observed in the cromakalim chroman nucleus provides compounds with desired antihypertensive activity free of the side effects commonly associated with P-blockers. Enantiomerically pure cromakalim is produced by resolution of the diastereomeric (T)-a-meth5lben2ylcarbamate derivatives. X-ray crystallographic analysis of this diastereomer provides the absolute stereochemistry of cromakalim. Biological activity resides primarily in the (—)-(33, 4R)-enantiomer [94535-50-9] (137) (108). In spontaneously hypertensive rats, the (—)-(33, 4R)-enantiomer, at dosages of 0.3 mg/kg, lowers the systoHc pressure 47%, whereas the (+)-(3R,43)-enantiomer only decreases the systoHc pressure by 14% at a dose of 3.0 mg/kg. 

In addition to the mechanism involving cycHc AMP, nonsugar sweeteners, eg, saccharin and a guanidine-type sweetener, have been found to enhance the production of another second messenger, inositol 1,4,5-trisphosphate (IP3), causing the closure of potassium channels and the release of... 

The resting membrane potential of most excitable cells is around —60 to —80 mV. This gradient is maintained by the activity of various ion channels. When the potassium channels of the cell open, potassium efflux occurs and hyperpolari2ation results. This decreases calcium channel openings, which ia turn preveats the influx of calcium iato the cell lea ding to a decrease ia iatraceUular calcium ia the smooth muscles of the vasculature. The vascular smooth muscles thea relax and the systemic blood pressure faUs. 

Vasodilators having potassium channel opener activity relax smooth muscle ia low (5—20 mM) K+ coaceatratioa but aot ia high (>80 mAf)K + solutioa, and glibenclamide [10238-21-8] should be able to reverse the iaduced relaxation (242,245—249). They also iacrease potassium efflux. 

There are at least 13 primary types of K+ channels known. In addition, within each type there are several subtypes. The best known chemical classes of potassium channel openers are nicorandil, piaacidil, and cromakalim. They are aU potent smooth muscle relaxants. PharmacologicaUy, they behave as classical vasodilators, lowering blood pressure and causiag tachycardia and fluid retention. 

Nicorandil. Nicorandil is a potassium channel opener that can lower blood pressure 21, 20, and 29 mm Hg after single oral doses of 10, 20, and 30 mg, respectively (250). There are no significant changes ia heart rate. Headache is the primary side effect. Nicorandil has potent coronary vasodilator effects. It causes sustained vasodilation of arteriolar resistance and venous capacitance blood vessels, thus reduciag cardiac preload and aftedoad. 

Pinacidil. Piaacidil is a poteat vasodilator, actiag through potassium channel opening effects (242,251—253). Its antihyperteasive effect is greater than that of hydrala2iae and pra2osia ia chronic treatmeat. Its fast oaset of actioa also makes it suitable for use ia hyperteasive crisis. 

Figure 12.9 Schematic diagram of the stmc-ture of a potassium channel viewed perpendicular to the plane of the membrane. The molecule is tetrameric with a hole in the middle that forms the ion pore (purple). Each subunit forms two transmembrane helices, the inner and the outer helix. The pore heJix and loop regions build up the ion pore in combination with the inner helix. (Adapted from S.A. Doyle et al., Science 280 69-77, 1998.)...

Doyle, D.A., et al. The structure of the potassium channel molecular basis of K+ conduction and selectivity. Science 280 69-77, 1998. 

MacKinnon, R., et al. Structural conservation in prokaryotic and eukaryotic potassium channels. Science 280 106-109, 1998. 

Back A hand-drawn image of the potassium channel, in the same view as on the front cover, with each subunit of the tetrameric protein shown in a different color. 

Dihydropyridine Z0947 (108) has been identified as a potassium channel opener for use in urinary urge incontinence and an asymmetric synthesis was required for long-... 

Packed column SFC has also been applied to preparative-scale separations [42], In comparison to preparative LC, SFC offers reduced solvent consumption and easier product recovery [43]. Whatley [44] described the preparative-scale resolution of potassium channel blockers. Increased resolution in SFC improved peak symmetry and allowed higher sample throughput when compared to LC. The enhanced resolution obtained in SFC also increases the enantiomeric purity of the fractions collected. Currently, the major obstacle to widespread use of preparative SFC has been the cost and complexity of the instrumentation. 

III Block of repolarizing potassium channels, prolongation of action potential Amiodarone, Dronedarone, Sotalol, Dofetilide, Ibutilide... 

Antidiabetic Drugs other than Insulin. Figure 1 Sulphonylureas stimulate insulin release by pancreatic (3-cells. They bind to the sulphonylurea receptor (SUR-1), which closes Kir6.2 (ATP-sensitive) potassium channels. This promotes depolarisation, voltage-dependent calcium influx, and activation of calcium-sensitive proteins that control exocytotic release of insulin. 

Potassium channel openers Hypertrichosis (minoxidil) lupus-like reactions and pedal edema (hydralazine)... 

Katp channels are the targets for two classes of therapeutic agents, hypoglycaemic drugs like glibencla-mide or nateglinide and potassium channel openers like... 

Schwanstecher C, Schwanstecher M (2002) Nucleotide sensitivity of pancreatic ATP-sensitive potassium channels and type 2 diabetes. Diabetes 51 (Suppl 3) S358-362... 

Additional cellular events linked to the activity of blood pressure regulating substances involve membrane sodium transport mechanisms Na+/K.+ ATPase Na+fLi countertransport Na+ -H exchange Na+-Ca2+ exchange Na+-K+ 2C1 transport passive Na+ transport potassium channels cell volume and intracellular pH changes and calcium channels. 

The CaR regulates numerous biological processes, including the expression of various genes (e.g., PTH) the secretion of hormones (PTH and calcitonin), cytokines (MCP-1), and calcium (e.g., into breast milk) the activities of channels (potassium channels) and transporters (aquaporin-2) cellular shape, motility (of macrophages), and migration cellular adhesion (of hematopoietic stem cells) and cellular proliferation (of colonocytes), differentiation (of keratinocytes), and apoptosis (of H-500 ley dig cancer cells) [3]. 

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