Three in one: inhibition of L-type CaV1.2 channels by Rem. Rem utilizes three distinct, but overlapping, mechanisms to inhibit CaV1.2 channel heterologously-expressed in HEK293 cells.4 Two of these modes, a reduction of channel membrane expression (N; red circle) and inhibition of pore opening (Po; blue circle), are dependent on an interaction with the channel β subunit.6 The third mode, in which the voltage-sensing elements of the channel are immobilized (Qmax; green circle), is facilitated by an interaction between the proximal amino-terminus (encompassing residues 93–153) of the α1C subunit of CaV1.2 and the distal carboxyl-terminus of Rem (residues 265–285).7 This latter form of inhibition specifically requires the Ras-like G domain of Rem, although the Rad G domain is likely capable of substituting for the Rem G domain. Gem and Rem2 operate only through β-dependent mechanisms.6,7