BK channel openers

Immunoreactivities of the SK1 and IK1 type of Ca2+-activated K+ channels were demonstrated to be down-regulated by chronic nerve injury thereby probably contributing to increased excitability in neuropathic states (Boettger et al., 2002). SK, IK (Jensen et al. (Neurosearch), 2000) and BK channel opening compounds (Sit and Meanwell (BMS), 1998 Hewawasam et al. (BMS), 1999 Hewawasam and Starrett (BMS), 2000) were claimed to be suitable for the treatment of migraine. 

Figure 16.16 Data from Kca1-ipi-subunit knockout (KO) mouse urinary bladder smooth muscle cells Indicate that the Kca1-1 (BK) channels from pi-subunlt KO mice have a reduced open probability compared to control (normal wild type) mouse. (A) Illustrates single channel recordings from excised Inside-out membrane patches (Section 16.5.1.3.) held at 40 and -i-40 mV In 10 gM free Ca + and symmetrical 60 gM K+ concentration. Arrows indicate the closed state of the channels. (B) illustrates BK channel open probability in control and pi-subunit KO animals at two different voltages (-40 and +40 mV). Data were obtained from n=9 11 cells of each animal group. Asterisks indicate statistically significant difference. Used with permission from Petkov et al., 2001a, J. Physiol. 537 443-452 - Copyright 2001 The Physiological Society.

Biological Applications Measuring membrane potential ion channel screening assays taste modulators screening assays detecting cystic fibrosis transmembrane conductance regulator (CFTR) HCN channel modulators BK channel openers ... 

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. 

Sanders Did you ever look to see whether indomethacin (i.e. prostaglandin inhibition) decreases coupling between these Ca2+ waves and activation of BK channels Perhaps this is your time delay. Production of prostaglandin should activate protein kinase A because of cAMP production, and this will increase BK open probability. 

A second family of K -channels comprises the Ca -sensitive K -channels - there are three recognized currents of this type. One, the high-conductance Ca -activated K -channel (Ibkicx)) - also called maxi-K channel, or BK channel - is blocked by TEA, Ba, quinine, tubocurarine, charybdotoxin, iberiotoxin, noxiustoxin, soyasaponin and penitrem A. This channel shows voltage-dependence, and the open-state probability of this large conductance channel increases with a rise in [Ca ] over the range O.l-lOpM, and... 

Voltage and calcium-activated channels BKca (7 helices), voltage sensitive and activated by direct binding of intracellular calcium IKca and SKca (6 helices), poorly sensitive to voltage and activated by calcium through catmoduline. BK and IK channels openers are studied in view of the prevention and treatment of cardiovascular disorders. 

Biological Applications Measuring membrane poten-tial potassium channel openers BK channel activator pyrophosphate assay ... 

Cukierman S, Krueger BK. 1990. Modulation of sodium channel gating by external divalent cations Differential effects on opening and closing rates. Pflugers Arch(Eur J Physiol) 416 360-367. 

Barlow RS, El-Mowafy AM, White RE. H2O2 opens BK(Ca) channels via the PLA2-arachidonic acid signaling cascade in coronary artery smooth muscle. Am J Physiol 2000 279 H475-H483. 

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