Endocrinology, Vol 136, 1530-1536, Copyright © 1995 by Endocrine Society

ARTICLES

Pituitary adenylate cyclase-activating polypeptide induces the voltage- independent activation of inward membrane currents and elevation of intracellular calcium in HIT-T15 insulinoma cells

CA Leech, GG Holz and JF Habener
Laboratory of Molecular Endocrinology, Howard Hughes Medical Institute, Harvard Medical School, Massachusetts General Hospital, Boston 02114.

The secretion of insulin by pancreatic beta-cells is controlled by synergistic interactions of glucose and hormones of the glucagon- related peptide family, of which pituitary adenylate cyclase-activating polypeptide (PACAP) is a member. Here we show by simultaneous recording of intracellular calcium ion ([Ca2+]i) and membrane potential that both PACAP-27 and PACAP-38 depolarize HIT-T15 cells and raise [Ca2+]i. PACAP stimulation can result in membrane depolarization by two distinct mechanisms: 1) PACAP reduces the membrane conductance and increases membrane excitability; and 2) PACAP activates a pronounced inward current that is predominantly a Na+ current, blockade by La3+, and which exhibits a reversal potential of about -28 mV. Activation of this current does not require membrane depolarization, because the response is observed when cells are held under voltage clamp at -70 mV. This current may result from the cAMP-dependent activation of nonspecific cation channels because the current is also observed in response to forskolin or membrane-permeant analogs of cAMP. We also suggest that PACAP raises [Ca2+]i and stimulates insulin secretion by three distinct mechanisms: 1) depolarization activates Ca2+ influx through L-type voltage-dependent calcium channels, 2) mobilization of intracellular Ca2+ stores, and 3) entry of Ca2+ via voltage-independent Ca2+ channels. These effects of PACAP may play an important role in a neuro- entero-endocrine loop regulating insulin secretion from pancreatic beta- cells during the transition period from fasting to feeding.

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