Calcium channel γ subunits: a functionally diverse protein family

Abstract

The calcium channel gamma subunits comprise an eight-member protein family that share a common topology consisting of four transmembrane domains and intracellular N- and C-termini. Although the first gamma subunit was identified as an auxiliary subunit of a voltage-dependent calcium channel, a review of phylogenetic, bioinformatic, and functional studies indicates that they are a functionally diverse protein family. A cluster containing gamma1 and gamma6 conforms to the original description of the protein family as they seem to act primarily as subunits of calcium channels expressed in muscle. Members of a second cluster (gamma2, gamma3, gamma4, gamma8) function as regulators of AMPA receptor localization and function in the brain and are collectively known as TARPs. The function of members of the third cluster (gamma5, gamma7) remains unclear. Our analysis shows that the members of each cluster contain conserved regulatory motifs that help to differentiate the groups. However, the physiological significance of these motifs in many cases remains to be demonstrated.

A Small Peptide Inhibitor of the Low Voltage-Activated Calcium Channel Cav3.1

“…A Peptide Inhibitor of the Cav3.1 Channel which changes the surface expression of the channel or voltage-dependence of activation and/or inactivation (for review, see Black, 2003;Dolphin, 2003;Klugbauer et al, 2003;Chen et al, 2007), this modulatory effect is rather unique. Lin et al (2008) have suggested that ␥ 6 can, with a critical GxxxA motif in TM1, trap the Cav3.1 channels in a less available state without changing the overall voltage-dependent open probability or single channel conductance.…”

“…In this scenario, modulation of ␥ 6 inhibition might provide an early and efficient way of enhancing LVA currents. Few known extra-or intracellular signaling sites exist in ␥ 6 (Chen et al, 2007). Research focused on revealing upstream signaling pathways that target ␥ 6 will help elucidate the biological roles of ␥ 6 under physiological or pathological conditions.…”

“…The auxiliary ␤ and ␣ 2 ␦ subunits positively regulate calcium current by promoting surface expression of the ␣ 1 subunit, enhancing voltage-dependent activation, and increasing channel open probability (Neely et al, 1993;Dolphin, 2003;Klugbauer et al, 2003). In contrast, our knowledge of the functions of the ␥ proteins as calcium channel auxiliary subunits is limited (Chen et al, 2007), and lacks mechanistic detail.…”

“…Although studies have shown that ␥ 2 , ␥ 3 , ␥ 4 , and ␥ 7 can modulate HVA calcium currents in heterologous expression systems (Black, 2003;Chen et al, 2007), attempts to demonstrate the influence of these ␥ subunits on HVA calcium current under physiological contexts (i.e., in neurons) have not been successful (Chen et al, 2000;Moss et al, 2002). Moreover, four of the eight subunits (␥ 2 , ␥ 3 , ␥ 4 , and ␥ 8 ) that contain a postsynaptic density 95/discs large/zona occludensbinding motif in their C termini have been found to primarily regulate AMPA receptors and are collectively named the transmembrane AMPA receptor regulatory proteins (TARPs, see Tomita et al, 2003).…”

Mutations in voltage-gated L-type calcium channel: implications in cardiac arrhythmia

“…The first γ 1 subunit was cloned from skeletal muscle [44,45], whereas it was not expressed in cardiac muscle [46]. The γ subunit distinguishingly modulates the functions by altering both activation and inactivation properties of LTCC [46].…”