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Comment
. 2005 Jan;115(1):16-20.
doi: 10.1172/JCI23970.

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

Shao-Nian Yang  1 , Per-Olof Berggren
Affiliations
Comment

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

Shao-Nian Yang et al. J Clin Invest. 2005 Jan.

Abstract

Insulin secretion is critically dependent on the proper function of a complex molecular network. Ca(V)2.3-knockout (Ca(V)2.3(-/-)) and PKClambda-knockout (PKClambda(-/-)) mouse models now suggest that these 2 players, the Ca(v)2.3 channel and PKClambda, are important constituents of this molecular network. Subsequent to glucose stimulation, insulin is released from the pancreatic beta cell in a biphasic pattern, i.e., a rapid initial phase followed by a slower, more sustained phase. Interestingly, Ca(2+) influx through the Ca(V)2.3 channel regulates only the second phase of insulin secretion. PKClambda seems to enter the beta cell nucleus and in turn modulates the expression of several genes critical for beta 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 beta 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 beta cell physiology and pathophysiology.

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Figures

Figure 1
Figure 1
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.
Figure 2
Figure 2
Ten isoforms of PKC with closely related kinase domains are classified into 3 subgroups: conventional PKC isoforms (PKCα, PKCβI, PKCβII, and PKCγ), novel PKC isoforms (PKCδ, PKCε, PKCη, and PKCθ), and atypical PKC isoforms (PKCζ and PKCι/λ). Multiple conventional PKC and novel PKC isoforms (c/n PKC) are involved in the regulation of insulin secretion through different _targets. PKCλ in the β cell is now shown to participate in glucose-stimulated insulin secretion by modulating the expression of HNF3β, hexokinase 1, hexokinase 2, glucose transporter 2, Kir6.2, and Sur1 subunit genes critical for β cell function. G, GTP-binding protein; GR, GTP-binding protein–coupled receptors; P, phosphoryl group; PB1, Phox and Bem 1; PDK-1, phosphatidylinositol 3-kinase-dependent kinase–1; PIP2, phosphatidylinositol 4,5-bisphosphate; PIP3, phosphatidylinositol 3,4,5-trisphosphate; PLC, phospholipase C; TKR, tyrosine kinase receptor.
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References

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