Voltage dependant calcium channels (VDCC) play a critical role in coupling electrical excitability to important physiological events such as secretion by neuronal and endocrine cells. Rem2, a GTPase restricted to neuroendocrine cell types, regulates VDCC activity by a mechanism that involves interaction with the VDCC β subunit (CaVβ). Mapping studies reveal that Rem2 binds to the guanylate kinase domain (GK) of the CaVβ subunit that also contains the high affinity binding site for the pore forming and voltage sensing VDCC α subunit (CaVα) interaction domain (AID). Moreover, fine mapping indicates that Rem2 binds to the GK domain in a region distinct from the AID interaction site, and competitive inhibition studies reveal that Rem2 does not disrupt CaVα - CaVβ binding. Instead, the CaVβ subunit appears to serve a scaffolding function, simultaneously binding both Rem2 and AID. Previous studies have found that in addition to CaVβ binding, Rem2 must be localized to the plasma membrane to inhibit VDCC function. Plasma membrane localization requires the C-terminus of Rem2 and binding studies indicate that this domain directs phosphorylated phosphatidylinositide (PIP) lipids association. Plasma membrane localization may provide a unique point of regulation since the ability of Rem2 to bind PIP lipids is inhibited by the phosphoserine dependant binding of 14-3-3 proteins. Thus, in addition to CaVβ binding, VDCC blockade by Rem2 is likely to be controlled by both the localized concentration of membrane PIP lipids and direct 14-3-3 binding to the Rem2 C-terminus.
|Number of pages||9|
|State||Published - Feb 2008|
Bibliographical noteFunding Information:
The authors wish to thank Amber Harper for excellent technical support. This work was supported by an American Diabetes Junior Faculty Award 7-05-JF-16 to (B.S.F.), Public Health Service Grants HL072936 (to D.A.A.) and HL074091 (to J.S.), a National Center for Research Resources grant P20 RR20171 (to D.A.A.), and an NIH Interdisciplinary Cardiovascular Training Grant T32 HL072743 (to R.N.C.).
ASJC Scopus subject areas
- Cell Biology