Expression of Rem2, an RGK Family Small GTPase, Reduces N-Type Calcium Current without Affecting Channel Surface Density

The RGK family of GTP-binding proteins: Regulators of voltage-dependent calcium channels and cytoskeleton remodeling

“…Indeed, Chen et al [49] reported that Rem2 does not affect the surface expression of endogenous N-type Ca 2+ channels in primary neurons, while Finlin et al [23,71] have reported similar finding for the regulation of endogenous L-type Ca 2+ channels by both Rem and Rem2 in HIT-T15 pancreatic β cells at a time when each RGK protein generates an almost complete block of Ca 2+ channel currents. Furthermore, cyclohexamide-mediated blockade of new Ca 2+ channel synthesis does not result in the inhibition of endogenous Ca 2+ currents seen following RGK expression in neurons [49], suggesting that the majority of RGK-mediated channel regulation in these cells is acute and not due to turnover of preformed channel complexes. Thus, while there is evidence to support a role for RGK proteins in VDCC trafficking, additional studies are needed to characterize the Ca 2+ channel subtypes that are subject to this mode of regulation, and whether additional cellular co-factors are required.…”

“…RGK proteins do not contain canonical lipid modification motifs [48], though there is enrichment of these proteins at the plasma membrane, and individual proteins have been shown to be localized to the cytosol, nucleus, and with both the actin and microtubule networks [4,5,18,41,43,44,[46][47][48][49][50][51][52][53][54]. The carboxyl terminus is well conserved (Fig.…”

“…The carboxyl terminus is well conserved (Fig. 1) and has been shown to play a critical role in the function of all RGK GTPases [49,55], regulating subcellular distribution [4,5,53], and directing protein-protein interactions [45,53,55], to control both Ca 2+ channel activity [49,53,55] and cytoskeletal reorganization [41][42][43][44]46,47,52]. This region contains a cysteine residue within a highly conserved domain termed the C-7 motif (Fig.…”

“…3). Ectopic expression of RGK proteins in variety of heterologous and endogenous cell models consistently demonstrates an almost complete inhibition of VDCC current, including L- [23,[52][53][54][55][70][71][72][73], P/Q- [52], and N- [49,52], but importantly not T-type channels which do not require accessory β-subunits for ionic current expression [55,69]. Recent studies in Xenopus oocytes demonstrate that this may be a dose-dependent effect [72], and recent work indicates that RGK-mediated Ca V β binding is essential for VDCC regulation [71].…”

“…However, the ability of RGK expression to alter Ca 2+ channel trafficking to date has only been directly demonstrated for L-type channels in heterologous expression systems [18,41,43,44,52]. Indeed, Chen et al [49] reported that Rem2 does not affect the surface expression of endogenous N-type Ca 2+ channels in primary neurons, while Finlin et al [23,71] have reported similar finding for the regulation of endogenous L-type Ca 2+ channels by both Rem and Rem2 in HIT-T15 pancreatic β cells at a time when each RGK protein generates an almost complete block of Ca 2+ channel currents. Furthermore, cyclohexamide-mediated blockade of new Ca 2+ channel synthesis does not result in the inhibition of endogenous Ca 2+ currents seen following RGK expression in neurons [49], suggesting that the majority of RGK-mediated channel regulation in these cells is acute and not due to turnover of preformed channel complexes.…”