Advances in Research on Pacemaking Function of Interstitial Cell of Cajal in Gastrointestinal Tract

Abstract

Most visceral smooth muscles, especially gastrointestinal (GI) smooth muscle, display spontaneous rhythmic contractions in the absence of neuronal or hormonal stimulation, which are associated with their physiological functions. The contractile behavior of gastrointestinal (GI) smooth muscles depends to a considerable extent on the intrinsic electrical activities of the muscles. This is particularly true of the phasic portions of the GI tract where cyclic depolarizations and repolarizations, referred to as slow waves, determine contractile frequency and maintain the phasic nature of contractions. Slow waves are of great functional importance because they determine the rate and timing of GI smooth muscle activity, and their impairment is likely to cause various motility disorders. GI smooth muscles exhibit a wide range of electrical behaviors (Szurszewski, 1987), and understanding the mechanisms of these events has been the goal of physiologists for more than half a century. Electrical activity can vary from slow changes in membrane potential, to hyperpolarization and depolarization responses to neurotransmitters, to oscillatory slow wave activity, to fast Ca2+ action potentials. All this behavior can be recorded during impalements of a single smooth muscle cell, which suggests that a plethora of ionic conductances and regulatory mechanisms are at play in GI muscles. Such diversity is almost unprecedented in other excitable cells. Diversity, the small size of smooth muscle cells, and the structural complexities of GI muscles have slowed progress toward understanding the ionic basis for electrical rhythmicity. The electrical output of GI muscles is a product of contributions from two electrically coupled cell types, smooth muscle cells and interstitial cells of Cajal (ICC) (Sanders,1996). These cells have distinct electrical missions and express different types of ionic conductances to accomplish those tasks. ICC generate slow waves and conduct them into adjacent smooth muscle cells to generate spontaneous contractions (Sanders, 1996; Thuneberg et al, 1982; Huizinga et al, 1995; Koh et al, 1998; Sanders et al, 1999). Smooth muscle cells respond to the depolarization/repolarization cycle imposed by ICC. Regulatory input from nerves, hormones, and paracrine substances are superimposed upon the ongoing myogenic activity. Responses to biologically active substances result from modulations of ionic conductances that are already active and going through dynamic changes in open probability during the slow wave cycle and from activation of new