Uncoupling of calcium mobilization and entry pathways in endothelin-stimulated pituitary lactotrophs.
In cells expressing Ca2+-mobilizing receptors, InsP3-induced Ca2+ release from intracellular stores is commonly associated with extracellular Ca2+ influx. Operation of these two Ca2+ signaling pathways mediates thyrotropin-releasing hormone (TRH) and angiotensin II (AII)-induced prolactin secretion from rat pituitary lactotrophs. After an initial hyperpolarization induced by Ca2+ mobilization from the endoplasmic reticulum (ER), these agonists generated an increase in the steady-state firing of action potentials, further facilitating extracellular Ca2+ influx and prolactin release. Like TRH and AII, endothelin-1 (ET-1) also induced a rapid release of Ca2+ from the ER and a concomitant spike prolactin secretion during the first 3-5 min of stimulation. However, unlike TRH and AII actions, Ca2+ mobilization was not coupled to Ca2+ influx during sustained ET-1 stimulation, as ET-1 induced a long-lasting abolition of action potential firing. This lead to a depletion of the ER Ca2+ pool, a prolonged decrease in [Ca2+]i, and sustained inhibition of prolactin release. ET-1-induced inhibition and TRH/AII-induced stimulation of Ca2+ influx and hormone secretion were reduced in the presence of the L-type Ca2+ channel blocker, nifedipine. Basal [Ca2+]i and prolactin release were also reduced in the presence of nifedipine. Furthermore, TRH-induced Ca2+ influx and secretion were abolished by ET-1, as TRH was unable to reactivate Ca2+ influx and prolactin release in ET-1-stimulated cells. Depolarization of the cells during sustained inhibitory action of ET-1, however, increased [Ca2+]i and prolactin release. These results indicate that L-type Ca2+ channel represents a common Ca2+ influx pathway that controls basal [Ca2+]i and secretion and is regulated by TRH/AII and ET-1 in an opposite manner. Thus, the receptor-mediated uncoupling of Ca2+ entry from Ca2+ mobilization provides an effective control mechanism in terminating the stimulatory action of ET-1. Moreover, it makes electrically active lactotrophs quiescent and unresponsive to other calcium-mobilizing agonists.
Lachowicz
A
A
Endocrinology and Reproduction Research Branch, NICHD, National Institutes of Health, Bethesda, Maryland 20892, USA.
Van Goor
F
F
Katzur
A C
AC
Bonhomme
G
G
Stojilkovic
S S
SS
D000200:Action Potentials / Q000187:drug effects; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D019332:Endothelin-1 / Q000494:pharmacology*; D005260:Female; D008564:Membrane Potentials / Q000187:drug effects; D009543:Nifedipine / Q000494:pharmacology; D010903:Pituitary Gland, Anterior / Q000166:cytology / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D011388:Prolactin / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013973:Thyrotropin-Releasing Hormone / Q000494:pharmacology
D002121:Calcium Channel Blockers; D015220:Calcium Channels; D019332:Endothelin-1; D000804:Angiotensin II; D013973:Thyrotropin-Releasing Hormone; D011388:Prolactin; D009543:Nifedipine; D002118:Calcium