Interstitial cells, drivers of smooth muscle function

Kenton M. Sanders, Sal A. Baker and Sean M. Ward

Department of Physiology and Cell Biology

University of Nevada, Reno School of Medicine

Reno, NV 89511

Traditional reviews and courses on the physiology of gastrointestinal (GI) motility have stressed ‘myogenic’ and ‘neurogenic’ mechanisms of regulation.  However, now it is known that features long-considered part of myogenic regulation are more complex.   In fact, smooth muscle cells (SMCs) in the gastrointestinal (GI) tract do not function in isolation.  Populations of interstitial cells (interstitial cells of Cajal (ICC) and PDGFRa⁺ cells) make gap junctions with SMCs, forming a super-syncytium known as the SIP syncytium.  ICC and PDGFRa⁺cells display spontaneous Ca²⁺ release events that activate signature conductances expressed by these cells, ANO1 in ICC and SK3 in PDGFRa⁺ cells.  Due to the electrical coupling, conductances activated in ICC and PDGFRa⁺ cells conduct to SMCs and affect the excitability and excitation-contraction coupling of the musculature.  A specific property of some ICC is generation of pacemaker activity that causes periodic depolarizations to conduct through the SIP syncytium.  These events, known as slow waves, have a complex mechanism and conductances not present in SMCs.  Thus, slow waves conduct passively to SMCs and cause depolarizations superimposed upon resting potentials.  Depolarization of SMCs activates voltage-dependent L-type Ca²⁺ channels, Ca²⁺ entry and excitation-contraction coupling.  This mechanism is responsible for development and propagation of rhythmic, phasic contractions that constitute peristalsis and segmentation in GI organs.  Thus, ICC are responsible for the patterned contractions of GI motility.  Neural inputs are largely transduced by ICC and PDGFRa⁺ cells and not directly by SMCs.  ICC express specific receptors and signaling mechanisms to facilitate motor neurotransmission.  Dominant motor neurotransmitters, acetylcholine (ACh) or nitric oxide (NO), enhance or depress Ca²⁺ release and activation of ANO1 channels, respectively.  PDGFRa⁺ cells express receptors and signaling pathways to transduce purinergic and peptidergic inhibitory neurotransmission.  Recent evidence also suggests inputs from multiple GI hormones are also transduced by interstitial cells.  Together, inputs from ICC and PDGFRa⁺ cells tune the excitability of GI SMCs to enhance or depress propagating phasic contractions or modulate the tonic contractions of sphincters.  GI motor patterns, originate in and are regulated by the integrated behaviors of the SIP syncytium.