Table of Contents
Journal of Signal Transduction
Volume 2012, Article ID 505346, 8 pages
http://dx.doi.org/10.1155/2012/505346
Research Article

Elimination of the Actin-Binding Domain in Kelch-Like 1 Protein Induces T-Type Calcium Channel Modulation Only in the Presence of Action Potential Waveforms

1Neuroscience Graduate Program, Loyola University Chicago, Chicago, IL 60153, USA
2Department of Neuroscience, Kennedy Center, Albert Einstein College of Medicine, Room 610, 1300 Morris Park Avenue, NY 10461, USA
3Institute of Human Genetics, University of Minnesota, MMC 206, 420 Delaware Street SE, Minneapolis, MN 55455, USA
4Office of Research Services, Room 4601, Building 102, 2160 S. First Avenue, Maywood, IL 60153, USA
5Cellular and Molecular Physiology Department, Stritch School of Medicine, Loyola University Chicago, Room 4669, Building 102, 2160 S. First Avenue, Maywood, IL 60153, USA
6Neuroscience Institute, Stritch School of Medicine, Loyola University Chicago, Room 4669, Building 102, 2160 S. First Avenue, Maywood, IL 60153, USA

Received 6 April 2012; Accepted 30 May 2012

Academic Editor: Jesus Garcia

Copyright © 2012 Kelly A. Aromolaran et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

The Kelch-like 1 protein (KLHL1) is a neuronal actin-binding protein that modulates calcium channel function. It increases the current density of Cav3.2 (α1H) calcium channels via direct interaction with α1H and actin-F, resulting in biophysical changes in Cav3.2 currents and an increase in recycling endosomal activity with subsequent increased α1H channel number at the plasma membrane. Interestingly, removal of the actin-binding Kelch motif (ΔKelch) prevents the increase in Cav3.2 current density seen with wild-type KLHL1 when tested with normal square pulse protocols but does not preclude the effect when tested using action potential waveforms (AP). Here, we dissected the kinetic properties of the AP waveform that confer the mutant Kelch the ability to interact with Cav3.2 and induce an increase in calcium influx. We modified the action potential waveform by altering the slopes of repolarization and/or recovery from hyperpolarization or by changing the duration of the depolarization plateau or the hyperpolarization phase and tested the modulation of Cav3.2 by the mutant ΔKelch. Our results show that the recovery phase from hyperpolarization phase determines the conformational changes that allow the α1H subunit to properly interact with mutant KLHL1 lacking its actin-binding Kelch domains, leading to increased Ca influx.