After prolonged incubation of target cells with hormones or neurotransmitters, the cellular responses are often blunted, a phenomenon generally referred to desensitization. In rat parotid acinar cells, desensitization of substance P-induced inos itol 1, 4, 5-trisphosphate (IP
3) formation has been documented. Substance P stimulation does not, however, inducea loss of responsiveness to muscarinic cholinergic stimulation in these same cells. The desensitization of the substance P response occurs within 10 sec after the addition of the peptide and essentially completed by 1 min. Desensitization is generally divided into two categories : one form is the homologous desensitization, in which only agonists specific to the receptor act as the desensitizing agent. The other form is heterologous which is characterized by diminished responsiveness to agonist for different receptor pathways, which is linked to the same signalling pathway : The desensitization of the substances P-induced IP
3 response is parallelled by a lossof specific binding sites for substance P. Thus the homologous desensitization apparently involves down-regulation of the substance P receptor. The substance P receptors are coupled to GTP binding protein. However, the GTP binding protein may not be related to the desensitization, because the effect of GTP
γS was not desensitized in the permeabilized-cells which had been desensitized to substance P. The recovery of the binding sites as wellas the recovery of the responsiveness to substance P is slow, requiring 1-2h. As a kind of feedback system, the protein kinase C may inhibit Ca
2+-mobilizing receptor systems. Phorbol esters, exclusiveactivators of protein kinase C, inhibited substance P-induced IP
3 formation. However, the loss of substance P receptors was not induced by the phorbol ester. Inhibitors of protein kinase C inhibited the effect of phorbol ester, but not the desensitization. These results suggest that the desensitization of substance P is not related to the protein kinase C-system.
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