Role of interstitial cells in enteric motor neurotransmission

It is now recognized that the motility of the GI tract is not determined only by myogenic and neurogenic mechanisms. At least 2 classes of interstitial cells lie in close proximity to varicose terminals of motor neurons and appear to mediate part of the response to neural input. The first group of cells is known as interstitial cells of Cajal (ICC). These cells course along the projections of motor neurons and make frequent very close contacts with nerve terminals. Loss of ICC in mutant mice, such as W/WV, let to reduced nitrergic and cholinergic post-junctional electrophysiological responses. More recently contractile responses to nerve stimulation have shown that nitrergic responses are greatly diminished when loss of intramuscular ICC (ICC-IM) is significantly reduced, however cholinergic contractile responses can actually increase when ICC-IM are reduced in number. The latter appears to be due to recruitment of Ca2+ sensitization mechanisms not typically employed in wildtype muscles. Recent cell-specific genetic deactivation experiments suggest that nitrergic responses are mediated by both smooth muscle cells (SMCs) and ICC, creating a parallel pattern of innervation. Another group of cells, known as PDGFR+ cells, has received attention recently. These cells are intertwined with nerve processes in close proximity to terminals. PDGFR+ cells express P2Y1 receptors and small-conductance Ca2+−activated K+ channels (SK3) that mediate purinergic inhibitory responses in GI muscles. Purine neurotransmitter substances and P2Y1-specific agonists activate Ca2+ transients in PDGFR+ cells in situ and Ca2+−activated K+ currents with properties of SK currents in isolated cells under voltage-clamp. Responses to purines are blocked by P2Y1 receptor antagonists and in P2ry1−/− mice. Nerve stimulation in intact muscles causes Ca2+ transients in PDGFR+ cells that are initiated with the same latency as purinergic inhibitory junction potentials. Responses in nearby SMCs are delayed until after initiation of the increase in Ca2+ transients in PDGFR+ cells and the SMC response is typically a small decrease in [Ca2+]i. These data are consistent with a model in which purinergic responses are initiated in PDGFR+ cells and conduct to SMCs. Together SMCs, ICC and PDGFR+ cells form an electrically coupled network of cells at terminals of enteric motor neurons. We have referred to this as the SIP syncytium, and motor responses in GI muscles are the integrated result of responses evoked by neurotransmitters in each of the SIP cells. (Supported by NIDDK P01 DK41315)