Premium
SECOND MESSENGERS AND THE REGULATION OF CA 2+ FLUXES BY CA 2+ ‐MOBILIZING AGONISTS IN RAT LIVER
Author(s) -
ALTIN JOSEPH G.,
BYGRAVE FYFE L.
Publication year - 1988
Publication title -
biological reviews
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.993
H-Index - 165
eISSN - 1469-185X
pISSN - 1464-7931
DOI - 10.1111/j.1469-185x.1988.tb00670.x
Subject(s) - second messenger system , diacylglycerol kinase , cytosol , microbiology and biotechnology , chemistry , agonist , receptor , intracellular , protein kinase c , signal transduction , biology , biophysics , biochemistry , enzyme
Summary Knowledge of the mechanism of action of Ca 2+ ‐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 PIP 2 and the generation of the second messengers diacylglycerol and IP 3 , for the activation of protein kinase C and the mobilization of intracellular Ca 2+ , respectively. Although the second messenger functions of diacylglycerol and IP 3 in these actions seem well established, it is not yet clear how the agonists are able to regulate Ca 2+ 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 Ca 2+ , Whilst there is evidence for the existence of more than one pathway for Ca 2+ influx in liver, it appears that in each instance the Ca 2+ influx process is regulated differently to the Ca 2+ influx through the volage‐sensitive Ca 2+ channels that is known to occur in excitable tissues. At present it is not clear whether any of the Ca 2+ 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 IP 3 and IP 4 in the regulation of Ca 2+ influx. The mechanism by which IP 3 and IP 4 may regulate Ca 2+ influx remains to be established, but it has been proposed that Ca 2+ entry into the cell occurs through a pathway connecting the plasma membrane and the endoplasmic reticulum, following the release of intracellular Ca 2+ from the lumen of the endoplasmic reticulum. Although it is not yet known whether glucagon (or cyclic AMP) activates the same pathway for Ca 2+ influx as Ca 2+ ‐mobilizing agonists, the marked potentiation by cyclic AMP of the Ca 2+ influx induced by Ca 2+ ‐mobilizing agonists has provided a powerful system with which to study the regulation of Ca 2+ influx in liver. Whether this Ca 2+ influx process occurs through some ion exchange mechanism (such as Ca 2+ /Na + exchange) remains to be determined. Results from this study suggests that the Ca 2+ influx is inhibited by neomycin, acidic pH, and a depolarization of the plasma membrane. The observation that cyclic AMP synergistically potentiates the influx of Ca 2+ induced by Ca 2+ ‐mobilizing agonists, that this influx appears to correlate with the reported ability of these agonists to induce PIP 2 hydrolysis and accumulation of IP 3 , and that cyclic AMP synergistically potentiates the production of IP 4 by vasopressin, are all consistent with the notion that IP 3 and IP 4 are involved in regulating Ca 2+ influx. Whilst little is known about the Ca 2+ transport process itself, these studies coupled with the recent finding that Ca 2+ 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.