Summary
I have been interested in smooth muscle physiology and pharmacology for most of my career. As a student, I became interested in electrical rhythmicity in smooth muscles, and I have devoted most of my efforts to trying to understand the mechanisms responsible for this activity. Like the heart, many smooth muscles have spontaneous rhythmicity. We now think that a special class of pacemaker cells, interstitial cells of Cajal (ICC), drives this activity in gastrointestinal smooth muscles and oviduct. I have collaborated with Drs. Sean Ward and Sang Don Koh for several years on the study of ICC. We have used electrophysiology, optical imaging techniques, molecular biology, confocal and electron microscopy, and several other techniques to study the structure and function of ICC. These cells are present in pacemaker areas of the GI tract and oviduct. ICC are excitable cells that are spontaneously active after they have been dispersed from intact muscles. We have made a transgenic mouse in which ICC are are labeled with a fluorescent protein (copGFP). The rhythmicity of GI and oviduct muscles stops when ICC are damaged or lost. We are also studying the development of ICC and trying to understand what happens to these cells in certain types of GI motility disorders, such as the defects in motility that occurs in diabetes. Look at our reviews in Gastroenterology (111:492-515, 1996) or Neurogastroenterology and Motility (11:311-38, 1999, and Ann Rev Physiology (68:307-43, 2006). if you want to learn more about ICC and the progress that has been made on these cells.
I've also been interested in neural control of smooth muscles. In the case of GI muscles important behaviors of intact organs and tissues are controlled by excitatory and inhibitory motor neurons. We have spent considerable effort trying to understand how the transmitter substances released by neurons affects electrical rhythmicity, intracellular calcium transients, and contractions. We have studied the effects of nitric oxide (NO) broadly and characterized post-junctional responses and molecular regulation of ion channels in response to NO released from neurons. Recently we have also been working on the other major inhibitory neurotransmitter, a purine, which for many years has been thought to be ATP. We have recently reported that B-NAD is actually a better candidate for this transmitter as the effects of exogenous ATP do not mimic the effects of the substance released from neurons. We also now recognize that ICC are innervated and participate in neurotransmission in GI muscles. Thus, loss of these cells may reduce regulation of GI motility by excitatory and inhibitory nerves. Much of our work on the role of neurotransmitters has focused on how these substances affect the ionic conductances in smooth muscle cells or ICC that are responsible for electrical responses. We have used the patch clamp technique extensively for these studies and molecular techniques to attempt to understand the targets of neurotransmitter actions.