Cyclic GMP regulates activation of phosphoinositidase C by bradykinin in sensory neurons.
Prior exposure of cultured neonatal rat dorsal root ganglion (DRG) neurons to bradykinin resulted in marked attenuation of bradykinin-induced activation of phosphoinositidase C (PIC). The (logconcentration)-response curve for bradykinin-induced [3H]inositol trisphosphate ([3H]IP3) formation was shifted to the right and the maximum response was reduced. Bradykinin increases cyclic GMP (cGMP) in DRG neurons [Burgess, Mullaney, McNeill, Coote, Minhas and Wood (1989) J. Neurochem. 53, 1212-1218] and treatment of the neurons with dibutyryl cGMP (dbcGMP) had a similar, inhibitory, effect on bradykinin-induced [3H]IP3 formation. NG-Nitro-L-arginine (LNNA) blocked bradykinin-induced formation of cGMP. It prevented the functional uncoupling induced by pretreatment with bradykinin, but not the inhibitory effect of dbcGMP on [3H]IP3 formation. The ability of LNNA to prevent desensitization was reversed by excess L-arginine, indicating that its actions were mediated through inhibition of nitric oxide synthase. In addition to functional desensitization, exposure to bradykinin reduced the number of cell-surface receptors detected with [3H]bradykinin, without affecting its KD value for the remaining sites. In contrast to bradykinin, pretreatment with dbcGMP had no effect on either the KD or B(max) for [3H]bradykinin binding. This implies that the inhibitory effect of dbcGMP was down-stream from the binding of bradykinin to its receptor and upstream of IP3 formation. The lack of effect of dbcGMP on [3H]bradykinin binding suggests that the decrease in receptor number induced by bradykinin was mediated by a different mechanism and was not a key factor in the rapid phase of desensitization in these cells.
Harvey
J S
JS
Sandoz Institute for Medical Research, London, U.K.
Burgess
G M
GM
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001920:Bradykinin / Q000378:metabolism / Q000494:pharmacology*; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000378:metabolism*; D003995:Dibutyryl Cyclic GMP / Q000494:pharmacology; D004789:Enzyme Activation; D005727:Ganglia, Spinal; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D009475:Neurons, Afferent / Q000201:enzymology*; D009478:Neuropeptide Y / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D019335:Nitroarginine; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D051381:Rats
D009478:Neuropeptide Y; D019335:Nitroarginine; D003995:Dibutyryl Cyclic GMP; D015544:Inositol 1,4,5-Trisphosphate; D001120:Arginine; D019001:Nitric Oxide Synthase; D010727:Phosphoric Diester Hydrolases; C021491:glycerophosphoinositol glycerophosphodiesterase; D006152:Cyclic GMP; D001920:Bradykinin