Potassium Channels And Their Modulators

Author : David Paul Jenkins
Publisher :
ISBN 13 : 9781267759078
Total Pages : pages
Book Rating : 4.7/5 (59 download)

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Download or read book Modulators of Small and Intermediate Conductance Calcium-activated Potassium Channel written by David Paul Jenkins and published by . This book was released on 2012 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: Ion channels generate the electrical signaling activity essential for complex life forms. Of prime importance, potassium channels establish and maintain the resting membrane potentials upon which cellular signaling dynamics are based. Potassium channels are the most diverse group of ion channels, offering great potential for selective interventions. Understanding the molecular, cellular and integrative physiology of potassium channels is critical for developing novel therapeutics. This dissertation examines the physiological roles of small- and intermediate-conductance calcium-activated potassium channels (K[subscript Ca]2/3) and the effects of their pharmacological modulation. Using a progressive chimeric approach and point-mutations, we delineated the site-of-action of NS8593, a selective negative gating modulator of K[subscript Ca]2 channels. Two residues, Ser-507 and Ala-532, adjacent to the cytoplasmic side of the selectivity filter mediate the action of NS8593. This demonstrates a site-of-action distinct from the positive gating modulators and suggests that negative gating modulation may result from a direct interaction with the physical gate of K[subscript Ca]2 channels. It further suggests that this type of gating modulation should be possible in other potassium and possibly in the related sodium and calcium channels. We identified and characterized a novel and structurally unique K[subscript Ca]3.1 blocker, NS6180, which compares favorably with the widely used TRAM-34. In heterologous expression systems and in native tissues, NS6180 inhibits K[subscript Ca]3.1 as potently (10-20 nM) as standard K[subscript Ca]3.1 blocker TRAM-34, and shares the same site-of-action, Thr-250 and Val-275. Despite these similarities, NS6180 has a distinct selectivity profile from TRAM-34, particularly showing significantly less inhibition of K[subscript V]7.2+7.3 channels. Finally, NS6180 produces immunosuppressive and anti-inflammatory effects in isolated splenocytes and DNBS induced rat colitis, demonstrating its promise for future development as a treatment of intestinal inflammation. Using optical mapping, we investigated the effects of NS8593 on action potential duration (APD) and effective refractory period (ERP) in isolated right atria from rabbits with chronic heart failure (CHF). APD was significantly decreased in CHF atria, while ERP was increased. NS8593 did not significantly affect ERP; however, it completely reversed the effects of CHF, restoring APD to control values. We have demonstrated that shortening of atrial action potentials secondary to chronic heart failure can be reversed by inhibition of K[subscript Ca]2 channels with the negative gating modulator, NS8593.