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

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.

Figure 1

The functional Ca_V channel consists of pore-forming subunits Ca_Vα1 and auxiliary subunits Ca_Vβ, Ca_Vα2/δ, and Ca_Vγ. Four types of Ca_Vα₁ subunits, designated Ca_V1.2, Ca_V1.3, Ca_V2.1, and Ca_V2.3, 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 K_ATP channel–dependent mechanisms trigger first-phase insulin secretion from the IRP by opening Ca_V1.2 and Ca_V1.3 channels. The K_ATP 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 Ca_V2.3 channels is now demonstrated to play a prominent role in second-phase insulin secretion. Ca_V1.2/1.3, Ca_V1.2 channels or Ca_V1.3 channels; Ca_V2.3, Ca_V2.3 channels; Depol, depolarization; GLUT2, glucose transporter 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.