Second messengers involved in the mechanism of action of bradykinin in sensory neurons in culture.
Application of bradykinin to neonatal rat dorsal root ganglion neurons caused a depolarization associated with an inward current and an increase in membrane conductance that was probably due to the opening of sodium channels. No hyperpolarization or outward current was detected. In addition, bradykinin increased the rate of 45Ca uptake into the neurons by a mechanism that was blocked by the dihydropyridine calcium channel antagonist nifedipine. Direct activation of protein kinase C (PKC) with phorbol esters mimicked the ability of bradykinin to depolarize the neurons and to increase the rate of 45Ca uptake. Down-regulation of PKC by prolonged treatment with phorbol esters and treatment of the cells with staurosporine, which inhibits PKC, blocked both bradykinin- and phorbol ester-induced 45Ca influx, and substantially reduced the proportion of cells that gave electrophysiological responses to either agent. Bradykinin also activated polyphosphoinositidase C in the dorsal root ganglion neurons, elevating levels of inositol(1,4,5)-trisphosphate and 1,2-diacylglycerol, an endogenous activator of PKC. It is suggested, therefore, that PKC may mediate some of the effects of bradykinin in sensory neurons.
Burgess
G M
GM
Sandoz Institute for Medical Research, London, United Kingdom.
Mullaney
I
I
McNeill
M
M
Dunn
P M
PM
Rang
H P
HP
D000818:Animals; D001696:Biomechanical Phenomena; D001920:Bradykinin / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism / Q000502:physiology; D002478:Cells, Cultured; D004594:Electrophysiology; D004789:Enzyme Activation; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects; D009475:Neurons, Afferent / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D015240:Phorbol 12,13-Dibutyrate / Q000494:pharmacology; D010716:Phosphatidylinositols / Q000378:metabolism; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology; D015290:Second Messenger Systems / Q000502:physiology*
D010716:Phosphatidylinositols; D015240:Phorbol 12,13-Dibutyrate; D011493:Protein Kinase C; D010727:Phosphoric Diester Hydrolases; C021491:glycerophosphoinositol glycerophosphodiesterase; D001920:Bradykinin; D002118:Calcium