Progression from homologous to heterologous desensitization of contractionin gastric smooth muscle cells

Acute desensitization of contraction and its relative mechanisms have been studied in smooth muscle cells isolated from guinea pig stomach. Desensitiz ation was induced by pre-exposure of the cells to one of the excitatory neu ropeptides linked to the phospholipase C intracellular cascade, i.e., chole cystokinin (CCK), gastrin-releasing peptide, and Substance P. Desensitizati on was homologous after a 30-s pre-exposure and heterologous if pre-exposur e lasted for 5 min or longer. Homologous desensitization was studied in a m ore detailed way after pre-exposure to CCK. Preincubation with increasing c oncentrations of CCK (10 pM-1 mu M) induced a progressive rightward shift o f the dose-response curves associated with both a decrease in potency (ED50 4.5 pM-2.2 nM) and a maximum response that were not related to a modificat ion of response kinetics. After brief pre-exposure to 1 nM CCK (D-max), an inhibition of contraction was observed in response to an identical dose of CCK (45.1 +/- 8.6%), the decreased response being associated with an inhibi tion of inositol phosphates and [Ca++](i) mobilization. Both inositol trisp hosphate (InsP(3))-induced contraction and [Ca++](i) mobilization were inhi bited to a lesser extent than CCK-induced responses. Any longer pre-exposur e of cells to one of the above-mentioned neuropeptides caused heterologous desensitization, with an observed inhibition of contraction in response to ail tested agonists (CCK, 60.3 +/- 5.9%; gastrin-releasing peptide: 56.7 +/ - 3.5%; Substance P, 60.6 +/- 6.5%). A similar decrease was observed in Ins P(3)-induced contractions resulting in a desensitization of the InsP(3) res ponse as well. Full recovery of contractile responses appeared within 30 mi n from the end of preincubation, thus indicating that degradation of membra ne receptors did not occur. Although pre-exposure of the cells to protein k inase C inhibitor GF109203X did not modify CCK-induced homologous desensiti zation, it blocked CCK-induced heterologous desensitization. This study dem onstrates that excitatory phospholipase C-coupled enteric neuropeptides ind uce a time-dependent homologous as well as heterologous desensitization of smooth muscle contraction occurring at receptor and postreceptor revels.