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Study Title:

The Modulation of Potassium Channels in the Smooth Muscle as a Therapeutic Strategy for Disorders of the Gastrointestinal Tract.

Study Abstract

Alterations of smooth muscle contractility contribute to the pathophysiology of important functional gastrointestinal disorders (FGIDs) such as functional dyspepsia and irritable bowel syndrome. Consequently, drugs that decrease smooth muscle contractility are effective treatments for these diseases. Smooth muscle contraction is mainly triggered by Ca(2+) influx through voltage-dependent channels located in the plasma membrane. Thus, the modulation of the membrane potential results in the regulation of Ca(2+) influx and cytosolic levels. K(+) channels play fundamental roles in these processes. The open probability of K(+) channels increases in response to various stimuli, including membrane depolarization (voltage-gated K(+) [K(V)] channels) and the increase in cytosolic Ca(2+) levels (Ca(2+)-dependent K(+) [K(Ca)] channels). K(+) channel activation is mostly associated with outward K(+) currents that hyperpolarize the membrane and reduce cell excitability and contractility. In addition, some K(+) channels are open at the resting membrane potential values of the smooth muscle cells in some gut segments and contribute to set the resting membrane potential itself. The closure of these channels induces membrane depolarization and smooth muscle contraction. K(V)1.2, 1.5, 2.2, 4.3, 7.4 and 11.1, K(Ca)1.1 and 2.3, and inwardly rectifying type 6K(+) (K(ir)6) channels play the most important functional roles in the gastrointestinal smooth muscle. Activators of all these channels may theoretically relax the gastrointestinal smooth muscle and could therefore be promising new therapeutic options for FGID. The challenge of future drug research and development in this area will be to synthesize molecules selective for the channel assemblies expressed in the gastrointestinal smooth muscle.

© 2016 Elsevier Inc. All rights reserved.

KEYWORDS:
Functional dyspepsia; Irritable bowel syndrome; K(2P) channels; K(Ca) channels; K(V) channels; K(ir) channels; Potassium channels