TY - JOUR T1 - A Small Peptide Inhibitor of the Low Voltage-Activated Calcium Channel Cav3.1 JF - Molecular Pharmacology JO - Mol Pharmacol SP - 1042 LP - 1051 DO - 10.1124/mol.108.052654 VL - 75 IS - 5 AU - Ren-Shiang Chen AU - Philip M. Best Y1 - 2009/05/01 UR - http://molpharm.aspetjournals.org/content/75/5/1042.abstract N2 - The calcium channel γ6 subunit modulates low voltage-activated (LVA) calcium current in both human embryonic kidney (HEK) cells and cardiomyocytes, although the mechanism of modulation is unknown. We recently showed that γ6 contains a critical GxxxA motif in the first transmembrane domain (TM1) that is essential for its inhibition of the Cav3.1 (LVA) calcium current. In this study, we tested the hypothesis that an eight-amino acid peptide that contains the GxxxA motif from γ6 TM1 can act as a novel pharmacological inhibitor of the Cav3.1 calcium current by performing whole-cell electrophysiology. Our results demonstrate that the peptide inhibits Cav3.1 current by dynamically binding and dissociating from the Cav3.1 channel in a concentration-dependent but largely voltage-independent manner. By selectively substituting residues within the peptide, we show that both the GxxxA framework and surrounding aliphatic side-chains contribute to the presumably interhelical interactions between γ6 TM1 and the Cav3.1 channel. The fast kinetics of the interaction supports the view that γ6 acts as an endogenous LVA channel antagonist within the plasma membrane, suggesting a mechanism other than regulation of surface expression or membrane trafficking of the poreforming subunit of the channel. We also demonstrate that the peptide has different affinities for Cav3.1 and Cav1.2 calcium currents, which is consistent with the selective effect of γ6 on LVA and high voltage-activated calcium currents in vivo. The American Society for Pharmacology and Experimental Therapeutics ER -