Uncoupling Secretion from Calcium

Science's STKE  26 Jul 2005:
Vol. 2005, Issue 294, pp. tw273
DOI: 10.1126/stke.2942005tw273

Regulated secretion occurs in response to increases in intracellular calcium concentration [Ca2+]i and underlies synaptic transmission and hormone release. Andric et al. found that endothelin (ET), acting through at least two G protein pathways, produces a bidirectional effect on pituitary lactotroph secretion of prolactin. Lactotrophs spontaneously fire action potentials, promoting calcium-induced basal secretion of prolactin. Addition of ET-1 to single lactotrophs produced an initial transient increase in secretion followed by a prolonged suppression below basal levels. The bidirectional effect of ET-1 on secretion was matched by a similar effect on [Ca2+]i--initially increasing [Ca2+]i, then decreasing [Ca2+]i. This was only observed for nanomolar concentrations of ET-1; subnanomolar concentrations only suppressed basal prolactin secretion without initially stimulating it and did not affect [Ca2+]i. The stimulatory phase of ET-1 activity was inhibited by addition of a phospholipase C inhibitor, consistent with involvement of Gq/11. Although pertussis toxin (an inhibitor of Gi/o) converted the ET-1 effect on [Ca2+]i to one of prolonged elevation, the effect on prolactin secretion was still bidirectional. Thus, the inhibition of secretion by ET-1 was independent from its effects on [Ca2+]i. Addition of phorbol ester to stimulate protein kinase C-dependent phosphorylation (Gαz is one target) inhibited the coupling of ET-1 to decreased adenosine 3′,5′-monophosphate (cAMP) concentration and prevented inhibition of prolactin secretion. Cells treated with antisense against Gαz showed a loss of suppression of prolactin secretion and an uncoupling from inhibition of adenylyl cyclase. Thus, ET-1 appears to regulate secretion using multiple G protein pathways. The Gαz pathway uncoupled secretion from [Ca2+]i, thereby inhibiting prolactin secretion without affecting pacemaking activity.

S. A. Andric, D. Zivadinovic, A. E. Gonzalez-Iglesias, A. Lachowicz, M. Tomic, S. S. Stojilkovic, Endothelin-induced, long lasting, and Ca2+ influx-independent blockade of intrinsic secretion in pituitary cells by Gz subunits. J. Biol. Chem. 280, 26896-26903 (2005). [Abstract] [Full Text]