Ca2+-mediated signalling

Voltage-gated K+ channels are critical to transmembrane potential- and Ca2+-mediated signalling. Voltage-regulated K+ channels are critically involved in action potentials as described above and such channels are blocked by the legume quinolizidine alkaloid sparteine (lupinidine) as well as by various synthetic psychoactive compounds with disparate effects such as amitryptiline, chlorpromazine, imipramine and phencyclidine. 

Ca2+ is a major second messenger in eukaryote cells, the cytosolic free concentration of Ca2+ being elevated in response to depolarization and to many hormones and NTs. Intracellular and PM voltage-gated Ca2+ channels are accordingly involved in Ca2+-mediated signalling. 

With calcineurin, a Ca2+-dependent protein phosphatase is involved, and thus it is possible to influence glycogen metabolism via Ca2+-mediated signals. 

As a-LTXN4C (see Section 2.3) does not form pores, it probably stimulates exocy-tosis by receptor mediated signaling. Therefore, the activity of a-LTXN4C has been investigated in Ca2+-dependent and Ca2+-independent exocytosis from neurons and Ca2+-dependent exocytosis from neuroendocrine cells. 

In the absence of Ca2+e, a-LTX only binds to LPH1 and PTPc. Ca2+-independent exocytosis requires the presence of Mg2+ and toxin insertion into the plasma membrane, but these conditions also induce formation of a-LTX channels. Influx of Na+ and efflux of K+ through these channels and associated efflux of small molecules and influx/efflux of water may cause secretion. In addition, transmitter release can be caused by membrane perturbation or direct interaction with secretory machinery. Some secretion may be nonvesicular. Receptor-mediated signaling can cause the activation of PKC in some cells. However, Ca2+-independent release is blocked by La3+, indicating that toxin pores play a crucial role in this release. 

Strock J, Diverse-Pierluissi MA (2004) Ca2+ channels as integrators of G protein-mediated signaling in neurons. Mol Pharmacol 66 1071-6... 

Sadoshima, J., Qiu, Z., Morgan, J.P., and Izumo, S. 1995. Angiotensin II and other hypertrophic stimuli mediated by G protein-coupled receptors activate tyrosine kinase, mitogen-activated protein kinase, and 90-kD S6 kinase in cardiac myocytes The critical role of Ca2+-dependent signaling. Circ. Res. 76 1-15. 

In this context interest is focused on PKC, which plays a key role in mediating signals generated by hormones, growth factors and neurotransmitters (Nishizuka, 1988). Several isoforms of PKC have been described which show distinct sensitivity to Ca2+ and phospholipid-degradation products (Nishizuka, 1988). Their specific function, however, is not defined. It has been demonstrated previously that phorbol esters are potent activators of PKC and induce inhibition of the catalytic domain of the insulin receptor probably via serine phosphorylation of the insulin receptor )8-subunit (Muller et al., 1991). 

Various feedback mechanisms exist that ensure a decrease in Ca2+ concentration and concomitant peak and wave formation under conditions of constant exposure to stimulatory signals. One example is provided by the Ca2+-dependence of subtypes of RGS proteins (Ishii et al., 2002) that can attenuate and shut down G protein-mediated signals. One of the effectors of Gq proteins is phospholipase Cfi, which stimulates Ca2+ release by InsP3 formation. Activation of Gq proteins by G protein-coupled receptors can be terminated by RGS proteins, subtypes of which are Ca2+/ calmodulin dependent. These RGS proteins are stimulated under conditions of high Ca2+ and will therefore inhibit further activation of phospholipase Cfi and the induction of InsP3/Ca2+ signals. 

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