Regulation of Non-selective Cation Conductances in GI Smooth Muscle

Project Leader: Sang Don Koh, M.D., Ph.D.

Abstract

The gastrointestinal tract mixes luminal contents and initiates the forward propulsion of luminal contents. This motor activity is regulated by both excitatory and inhibitory motor nerves as well as by pacemaker potentials generated by Interstitial Cells of Cajal (ICC). Smooth Muscle (SM) cells serve as the final effectors of motor activity. Regardless of the commands issued by enteric motor neurons and ICC, if SM excitability mechanisms are not functioning properly motor dysfunction will result. The ionic conductances that regulate resting membrane potential in smooth muscle cells are of central importance in the regulation of GI motility. The ionic mechanisms in the muscle play a fundamental role in setting the resting membrane potential and thus determining contractile activity. However, resting membrane potential is not determined solely by the activity of K+ channels. Inward currents, such as resting Na+ or Ca2+ conductance can shift the resting membrane potentials to values more positive than the K+ equilibrium potential. This leak current is thought to be due to the expression of a variety of different Non-selective Cation Channels (NSCC). Therefore the working hypothesis for this application is that NSCC, particularly the TRP family of proteins, play an important role in regulating resting membrane potential in colon and that the activity of these channels can be regulated by several different second messenger pathways or pathological conditions that alter contractile activity of the colonic muscle. Thus we will investigate the following specific aims.

• Aim 1: What are the electrophysiological properties of basally activated NSCC?
• Aim 2: What are the intracellular signaling mechanisms regulating basally activated NSCC?
• Aim 3: What are the molecular candidates for basally activated NSCC?
• Aim 4: What are the functional roles of basally activated NSCC in pathophysiological conditions?

In summary investigation of these hypotheses will aid our understanding of functional role of basally activated NSCC in relation to regulation of the resting membrane potentials in physiological and pathological conditions.