Editors' ChoiceCalcium

Novel Role for Calcium Channel β3 Subunit in Insulin Secretion

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Science's STKE  26 Oct 2004:
Vol. 2004, Issue 256, pp. tw385
DOI: 10.1126/stke.2562004tw385

The accessory β subunits of voltage-gated calcium channels regulate various aspects of channel activity, from delivery to the plasma membrane to the biophysical properties of the channel. Berggren et al. show that the β3 subunit of the L-type calcium channel serves to negatively regulate insulin secretion and that β3—/— mice had increased insulin secretion and more efficient glucose uptake than wild-type mice. Surprisingly, the biophysical properties and activity of the L-type Ca2+ channel in the knockout and wild-type pancreatic β cells were identical. Measurement of the changes in intracellular calcium concentration ([Ca2+]i) in response to high glucose indicated that a higher proportion of the knockout cells exhibited calcium oscillations and that the oscillations were a higher frequency than those observed in wild-type cells. Indeed repetitive depolarizations produced calcium oscillations and an increase in exocytotic activity (based on an increase in membrane capacitance), whereas a single-step depolarization produced a nonoscillating increase in [Ca2+]i and a smaller increase in exocytotic activity. The calcium oscillations seemed to be due to the release of calcium from internal stores, because pharmacological inhibition of the endoplasmic reticulum (ER) calcium pump or the inositol trisphosphate receptor (IP3R) altered the calcium signal. Islets from the knockout mice showed an increase in [Ca2+]i in response to stimulation of muscarinic acetylcholine receptors with carbachol, which couples to IP3 through the activation of phospholipase C. When the β3 subunit was transfected into cells that do not express the L-type calcium channel, IP3-induced increase in [Ca2+]i was decreased. Confocal microscopy of pancreatic β cells indicated that the β3 subunit was present on the ER adjacent to the IP3R, but the two proteins could not be coimmunoprecipitated; thus, it is not clear whether the regulation of IP3-stimulated calcium release by the β subunit is mediated by a direct interaction. Islets from the knockout mice showed increased IP3 production in response to carbachol. Thus, the β subunit appears to be a negative regulator of calcium signaling in pancreatic β cells, and the mechanism may not involve the L-type calcium channel but rather may be mediated through regulation of release of calcium from internal stores. Although the exact mechanism remains to be determined, the β subunit may be an attractive target for increasing insulin release in diabetes.

P. O. Berggren, S. N. Yang, M. Murakami, A. M. Efanov, S. Uhles, M. Kohler, T. Moede, A. Fernstrom, I. B. Appelskog, C. A. Aspinwall, S. V. Zaitsev, O. Larsson, L. M. de Vargas, C. Fecher-Trost, P. Weissgerber, A. Ludwig, B. Leibiger, L. Juntti-Berggren, C. J. Barker, J. Gromada, M. Freichel, I. B. Leibiger, V. Flockerzi, Removal of Ca2+ channel β3 subunit enhances Ca2+ oscillation frequency and insulin exocytosis. Cell 119, 273-284 (2004). [Online Journal]

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