Calcium Channel Gamma(6) Subunit: In Search of Its Functions and Mechanisms of Action

Voltage-gated calcium channels contain a pore-forming alpha1 subunit and auxiliary alpha2delta, beta and gamma subunits. Of the three auxiliary subunits, gamma is least understood. Cardiac myocytes express three gamma isoforms: gamma4, gamma6 and gamma 7. Low-voltage activated (LVA) calcium currents regulate rhythmic activity and cell proliferation in the heart. Previous studies using heterologous expression systems showed that gamma6 robustly inhibits Cav3.1 current, which is a major LVA component in adult atrial myocytes. On the other hand, gamma4 and gamma7 do not inhibit Cav 3.1 currents. Using whole-cell electrophysiology, we demonstrated that gamma 6 also inhibits LVA currents in HL-1 cardiomyocytes, confirming its function in native cells. Previous studies from our lab indicated that the first transmembrane domain of gamma6 is responsible for its inhibitory function. Using mutational analysis, we further identified the first GxxxA motif in the first transmembrane domain of gamma6 as being essential for the interaction between gamma6 and Cav3.1. Our previous experiments also indicated that wild-type gamma1 does not inhibit Cav3.1 currents. In this study, a GxxxA motif was introduced into the first transmembrane domain of the gamma1 subunit. The introduced motif conferred Cav3.1 inhibitory function to gamma 1, confirming the essential role of the GxxxA motif. Taken together, our results demonstrated the inhibitory function of gamma6 on LVA currents in a cardiac background. We also identified the importance of the GxxxA motif in mediating the interaction between gamma6 and Cav3.1 subunits.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Neuroscience

Grantor

University of Illinois at Urbana-Champaign

Year dc:date

2015

Author dc:creator

• Chen, Ren-Shiang

Contributors dc:contributor

• Best, Philip M.

• Biology, Animal Physiology

Language dc:language

eng

Identifier

(MiAaPQ)AAI3242816

OAI identifier oai:identifier

oai:www.ideals.illinois.edu:2142/82508