Neuropeptide inhibition of voltage-gated calcium channels mediated by mobilization of intracellular calcium.
Many neurotransmitters and hormones regulate secretion from endocrine cells and neurons by modulating voltage-gated Ca2+ channels. One proposed mechanism of neurotransmitter inhibition involves protein kinase C, activated by diacylglycerol, a product of phosphatidyl-inositol inositol hydrolysis. Here we show that thyrotropin-releasing hormone (TRH), a neuropeptide that modulates hormone secretion from pituitary tumor cells, inhibits Ca2+ channels via the other limb of the phosphatidylinositol signaling system: TRH causes inositol trisphosphate-triggered Ca2+ release from intracellular organelles, thus causing Ca2(+)-dependent inactivation of Ca2+ channels. Elevation of intracellular Ca2+ concentration is coincident with the onset of TRH-induced inhibition and is necessary and sufficient for its occurrence. The inhibition is blocked by introducing Ca2+ buffers into cells and mimicked by a variety of agents that mobilize Ca2+. Treatments that suppress protein kinase C have no effect on the inhibition. Hence inactivation of Ca2+ channels occurs not only as a result of Ca2+ influx through plasma membrane channels, but also via neurotransmitter-induced Ca2+ mobilization. This phenomenon may be common but overlooked because of the routine use of Ca2+ buffers in patch-clamp electrodes.
Kramer
R H
RH
Howard Hughes Medical Institute, Columbia University, College of Physicians and Surgeons, New York, New York 10032.
Kaczmarek
L K
LK
Levitan
E S
ES
D002118:Calcium / Q000378:metabolism*; D015220:Calcium Channels / Q000187:drug effects*; D004594:Electrophysiology; D007425:Intracellular Membranes / Q000378:metabolism*; D015640:Ion Channel Gating / Q000502:physiology*; D009479:Neuropeptides / Q000494:pharmacology*; D011493:Protein Kinase C / Q000502:physiology; D013973:Thyrotropin-Releasing Hormone / Q000494:pharmacology
D015220:Calcium Channels; D009479:Neuropeptides; D013973:Thyrotropin-Releasing Hormone; D011493:Protein Kinase C; D002118:Calcium