Abstract
Spontaneous excitability and contractions of colonic smooth muscle cells (SMCs) are normally suppressed by inputs from inhibitory motor neurons, a behavior known as tonic inhibition. The post-junctional cell(s) mediating tonic inhibition have not been elucidated. We investigated the post-junctional cells mediating tonic inhibition in the proximal colon and whether tonic inhibition results from suppression of the activity of Ano1 channels, which are expressed exclusively in interstitial cells of Cajal (ICC). We found that tetrodotoxin (TTX), an inhibitor of nitric oxide (NO) synthesis, L-NNA, and an inhibitor of soluble guanylyl cyclase, ODQ, greatly enhanced colonic contractions. Ano1 antagonists, benzbromarone and Ani9 inhibited the effects of TTX, L-NNA and ODQ. Ano1 channels are activated by Ca2+ release from the endoplasmic reticulum (ER) in ICC, and blocking Ca2+ release with a SERCA inhibitor (thapsigargin) or a store-operated Ca2+ entry blocker (GSK 7975 A) reversed the effects of TTX, L-NNA and ODQ. Ca2+ imaging revealed that TTX, L-NNA and ODQ increased Ca2+ transient firing in colonic ICC. Our results suggest that tonic inhibition in the proximal colon occurs through suppression of Ca2+ release events in ICC. Suppression of Ca2+ release in ICC limits the open probability of Ano1 channels, reducing the excitability of electrically-coupled SMCs.
Highlights
Contractions of the smooth muscle cells (SMCs) in the proximal colon are essential for colonic motility that assists in reabsorption of water and electrolytes and eventually propels fecal materials toward the distal colon and rectum
Results are presented showing that nitrergic inputs suppress Ca2+ release events in interstitial cells of Cajal (ICC) in the proximal colon, and the enhancement in contractions elicited by blocking tonic inhibition are suppressed by Ano[1] channel antagonists
Phasic contractions were restrained by tonic inhibitory input from enteric neurons, because addition of TTX (1 μM) caused dramatic increases in contractions (Fig. 1A)
Summary
Contractions of the smooth muscle cells (SMCs) in the proximal colon are essential for colonic motility that assists in reabsorption of water and electrolytes and eventually propels fecal materials toward the distal colon and rectum. Contractions of the proximal colon are regulated by intrinsic and extrinsic motor neurons, but neural controls are superimposed upon myogenic mechanisms that set the excitability of SMCs. The term ‘myogenic’, once exclusive to the cellular mechanisms of SMCs, includes mechanisms attributed to interstitial cells, such as interstitial cells of Cajal (ICC) and platelet-derived-growth-factor-receptor-alpha+ (PDGFRα+) cells. The term ‘myogenic’, once exclusive to the cellular mechanisms of SMCs, includes mechanisms attributed to interstitial cells, such as interstitial cells of Cajal (ICC) and platelet-derived-growth-factor-receptor-alpha+ (PDGFRα+) cells Together these cells make up a complex of electrically-coupled cells, known collectively as the SIP syncytium[1,2]. Results are presented showing that nitrergic inputs suppress Ca2+ release events in ICC in the proximal colon, and the enhancement in contractions elicited by blocking tonic inhibition are suppressed by Ano[1] channel antagonists
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