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NEUROREGULATION AND MOTILITY

G protein-mediated dysfunction of excitation-contraction coupling in ileal inflammation

Departments of Internal Medicine, Physiology and Biophysics, Enteric Neuromuscular Disorders and Visceral Pain Center, Division of Gastroenterology, The University of Texas Medical Branch at Galveston, Galveston, Texas 77555-1064

Submitted 17 September 2003 ; accepted in final form 12 December 2003

Inflammation impairs the circular muscle contractile response to muscarinic (M) receptor activation. The aim of this study was to investigate whether the expression of muscarinic receptors, their binding affinity, and the expression and activation of receptor-coupled G proteins contribute to the suppression of contractility in inflammation. The studies were performed on freshly dissociated single smooth muscle cells from normal and inflamed canine ileum. Northern blotting indicated the presence of only M₂ and M₃ receptors on canine ileal circular muscle cells. Inflammation did not alter the mRNA or protein expression of M₂ and M₃ receptors. The maximal binding and K_d values also did not differ between normal and inflamed cells. However, the contractile response to ACh in M₃ receptor-protected cells was suppressed, whereas that in M₂ receptor-protected cells was enhanced. Further experiments indicated that the expression and binding activity of G_q/11 protein, which couples to M₃ receptors, were downregulated, whereas those of G_i3, which couples to M₂ receptors, were upregulated in inflamed cells. We concluded that inflammation depresses M₃ receptor function, but it enhances M₂ receptor function in ileum. These effects are mediated by the differentially altered expression and binding activity of their respective coupled G_q/11 and G_i3 proteins.

smooth muscle; motility; inflammatory bowel disease; signalopathy; acetylcholine

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