SECOND MESSENGERS AND THE REGULATION OF CA 2+ FLUXES BY CA 2+ ‐MOBILIZING AGONISTS IN RAT LIVER
Authors: ALTIN JOSEPH G. , BYGRAVE FYFE L. 
Published: January 2008

Knowledge of the mechanism of action of Ca2+‐mobilizing agonists in liver has progressed considerably following the discovery that their interaction with specific receptors on the plasma membrane is accompanied by the hydrolysis of PIP2 and the generation of the second messengers diacylglycerol and IP3, for the activation of protein kinase C and the mobilization of intracellular Ca2+, respectively. Although the second messenger functions of diacylglycerol and IP3 in these actions seem well established, it is not yet clear how the agonists are able to regulate Ca2+ influx across the plasma membrane, an event which is crucial for those actions of the agonists which are dependent on the maintenance of an elevated level of cytosolic Ca2+, Whilst there is evidence for the existence of more than one pathway for Ca2+ influx in liver, it appears that in each instance the Ca2+ influx process is regulated differently to the Ca2+ influx through the volage‐sensitive Ca2+ channels that is known to occur in excitable tissues. At present it is not clear whether any of the Ca2+ influx pathways in liver is regulated by direct coupling to the agonist receptor mechanism on the outer surface of the plasma membrane, or whether the regulation involves the production of some second messenger(s). However, indirect evidence from a number of tissues appears to favour the involvement of both IP3 and IP4 in the regulation of Ca2+ influx. The mechanism by which IP3 and IP4 may regulate Ca2+ influx remains to be established, but it has been proposed that Ca2+ entry into the cell occurs through a pathway connecting the plasma membrane and the endoplasmic reticulum, following the release of intracellular Ca2+ from the lumen of the endoplasmic reticulum.

Although it is not yet known whether glucagon (or cyclic AMP) activates the same pathway for Ca2+ influx as Ca2+‐mobilizing agonists, the marked potentiation by cyclic AMP of the Ca2+ influx induced by Ca2+‐mobilizing agonists has provided a powerful system with which to study the regulation of Ca2+ influx in liver. Whether this Ca2+ influx process occurs through some ion exchange mechanism (such as Ca2+/Na+ exchange) remains to be determined. Results from this study suggests that the Ca2+ influx is inhibited by neomycin, acidic pH, and a depolarization of the plasma membrane. The observation that cyclic AMP synergistically potentiates the influx of Ca2+ induced by Ca2+‐mobilizing agonists, that this influx appears to correlate with the reported ability of these agonists to induce PIP2 hydrolysis and accumulation of IP3, and that cyclic AMP synergistically potentiates the production of IP4 by vasopressin, are all consistent with the notion that IP3 and IP4 are involved in regulating Ca2+ influx. Whilst little is known about the Ca2+ transport process itself, these studies coupled with the recent finding that Ca2+ influx into the liver cell can occur through different pathways, seem set to lead to a better understanding of this important process in the near future.