AJP - Cell Physiology, Vol 273, Issue 2 C612-C617, Copyright © 1997 by American Physiological Society
Cholinergic modulation of the Ca2+ response to bradykinin in neuroblastoma cells
J. S. Coggan and S. H. Thompson
Department of Biological Sciences, Stanford University, Pacific Grove, California 93950, USA.
Fura 2 imaging was used to measure intracellular Ca2+ signals in N1E-115
mouse neuroblastoma cells during combined activation of bradykinin (BK) and
cholinergic receptors. BK and carbachol (CCh) both activate phospholipase C
(PLC) and cause Ca2+ release from inositol 1,4,5-trisphosphate
(IP3)-sensitive Ca2+ stores. The Ca2+ signal in response to CCh is
prolonged by the activation of Ca2+ influx, but BK does not appear to
activate the influx pathway. When BK and CCh are applied together (BK+CCh),
the Ca2+ response is composed of both Ca2+ release and Ca2+ influx. Ca2+
influx is also activated by BK+CCh in a subset of cells that does not
respond with a intracellular Ca2+ concentration increase when CCh is
presented by itself. This suggests that CCh stimulates a Ca(2+)-silent
cholinergic receptor that is not coupled to Ca2+ release but acts
synergistically with BK receptors to activate Ca2+ influx. Pertussis toxin
reduces influx without affecting release, indicating that the G protein
that modulates the influx pathway is different from the G protein
responsible for activating PLC. Cholinergic stimulation also causes
progressive heterologous desensitization of BK-evoked Ca2+ release.
Desensitization has the unique property of continuing to develop after the
cholinergic agonist is removed and the cholinergic Ca2+ response has fully
recovered. Heterologous desensitization is not the result of Ca2+ store
depletion or a long-lasting inhibition of PLC or IP3-dependent Ca2+
release. Instead, it appears to involve an early step in the BK-signaling
cascade, possibly at the level of the B2 receptor or associated G proteins.
