CaV2.3 channel and PKCλ: new players in insulin secretion
Shao-Nian Yang, Per-Olof Berggren
Shao-Nian Yang, Per-Olof Berggren
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Commentary

CaV2.3 channel and PKCλ: new players in insulin secretion

Abstract

Insulin secretion is critically dependent on the proper function of a complex molecular network. CaV2.3-knockout (CaV2.3–/–) and PKCλ-knockout (PKCλ–/–) mouse models now suggest that these 2 players, the Cav2.3 channel and PKCλ, are important constituents of this molecular network. Subsequent to glucose stimulation, insulin is released from the pancreatic β cell in a biphasic pattern, i.e., a rapid initial phase followed by a slower, more sustained phase. Interestingly, Ca2+ influx through the CaV2.3 channel regulates only the second phase of insulin secretion. PKCλ seems to enter the β cell nucleus and in turn modulates the expression of several genes critical for β cell secretory function. Studies by Hashimoto et al. and Jing et al. in this issue of the JCI set out to answer the question of why numerous isoforms of proteins with similar functions are present in the β cell. This is important, since it has been difficult to understand the modulatory and/or regulatory roles of different isoforms of proteins in defined subcellular compartments and at various times during the secretory process in both β cell physiology and pathophysiology.

Authors

Shao-Nian Yang, Per-Olof Berggren

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Figure 1

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The functional CaV channel consists of pore-forming subunits CaVα1 and a...
The functional CaV channel consists of pore-forming subunits CaVα1 and auxiliary subunits CaVβ, CaVα2/δ, and CaVγ. Four types of CaVα1 subunits, designated CaV1.2, CaV1.3, CaV2.1, and CaV2.3, conducting L-, P/Q-, and R-type Ca2+ currents, have been identified in the mouse β cell. Glucose-stimulated insulin secretion is characterized by a rapid first phase of insulin release for about 10 minutes, followed by a nadir, and subsequently a gradually increasing second phase reaching a plateau after 25 to 30 minutes (inset). Insulin-containing granules (IG) are functionally divided into three pools: the reserve pool (RP), the readily releasable pool (RRP), and the immediately releasable pool (IRP). The present consensus is that the KATP channel–dependent mechanisms trigger first-phase insulin secretion from the IRP by opening CaV1.2 and CaV1.3 channels. The KATP channel–independent mechanisms underlie second-phase insulin secretion by recruiting insulin-containing granules from RP and RRP to IRP. The Ca2+ influx through β cell CaV2.3 channels is now demonstrated to play a prominent role in second-phase insulin secretion. CaV1.2/1.3, CaV1.2 channels or CaV1.3 channels; CaV2.3, CaV2.3 channels; Depol, depolarization; GLUT2, glucose transporter 2.