Rem inhibits CaV1.2 channels via three mechanisms: reducing surface density, decreasing open probability, and immobilizing voltage sensors, requiring distinct GTPase conformations.
Rem inhibits Ca(V)1.2 channels through three distinct mechanisms, providing mechanistic insights that could inform the development of novel calcium channel blockers.
Rad/Rem/Gem/Kir (RGK) GTPases potently inhibit Ca(V)1 and Ca(V)2 (Ca(V)1-2) channels, a paradigm of ion channel regulation by monomeric G-proteins with significant physiological ramifications and potential biotechnology applications. The mechanism(s) underlying how RGK proteins inhibit I(Ca) is unknown, and it is unclear how key structural and regulatory properties of these GTPases (such as the role of GTP binding to the nucleotide binding domain (NBD), and the C-terminus which contains a membrane-targeting motif) feature in this effect. Here, we show that Rem inhibits Ca(V)1.2 channels by three independent mechanisms that rely on distinct configurations of the GTPase: (1) a reduction in surface density of channels is accomplished by enhancing dynamin-dependent endocytosis, (2) a diminution of channel open probability (P(o)) that occurs without impacting on voltage sensor movement, and (3) an immobilization of Ca(V) channel voltage sensors. The presence of both the Rem NBD and C-terminus (whether membrane-targeted or not) in one molecule is sufficient to reconstitute all three mechanisms. However, membrane localization of the NBD by a generic membrane-targeting module reconstitutes only the decreased P(o) function (mechanism 2). A point mutation that prevents GTP binding to the NBD selectively eliminates the capacity to immobilize voltage sensors (mechanism 3). The results reveal an uncommon multiplicity in the mechanisms Rem uses to inhibit I(Ca), predict new physiological dimensions of the RGK GTPase-Ca(V) channel crosstalk, and suggest original approaches for developing novel Ca(V) channel blockers.
Yang et al. (Tue,) conducted a other in CaV1.2 channel regulation. Rem (RGK GTPase) was evaluated on Mechanisms of CaV1.2 channel inhibition. Rem inhibits CaV1.2 channels via three mechanisms: reducing surface density, decreasing open probability, and immobilizing voltage sensors, requiring distinct GTPase conformations.
Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context: