T-type current modulation by the actin-binding protein Kelch-like 1

K. A. Aromolaran, K. A. Benzow, L. L. Cribbs, M. D. Koob, E. S. Piedras-Rentería

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22 Scopus citations

Abstract

We report a novel form of modulation of T-type calcium currents carried out by the neuronal actin-binding protein (ABP) Kelch-like 1 (KLHL1). KLHL1 is a constitutive neuronal ABP localized to the soma and dendritic arbors; its genetic elimination in Purkinje neurons leads to dendritic atrophy and motor insufficiency. KLHL1 participates in neurite outgrowth and upregulates voltage-gated P/Q-type calcium channel function; here we investigated KLHL1's role as a modulator of low-voltage-gated calcium channels and determined the molecular mechanism of this modulation with electrophysiology and biochemistry. Coexpression of KLHL1 with CaV3.1 or Ca+3.2 (α1G or α1H subunits) caused increases in T-type current density (35%) and calcium influx (75-83%) when carried out by α1H but not by α1G. The association between KLHL1 and α1H was determined by immunoprecipitation and immunolocalization in brain membrane fractions and in vitro in HEK-293 cells. Noise analysis showed that neither α1H single-channel conductance nor open probability was altered by KLHL1, yet a significant increase in channel number was detected and further corroborated by Western blot analysis. KLHL1 also induced an increase in α1H current deactivation time (τdeactivation). Interestingly, the majority of KLHL1's effects were eliminated when the actin-binding motif (kelch) was removed, with the exception of the calcium influx increase during action potentials, indicating that KLHL1 interacts with α1H and actin and selectively regulates α1H function by increasing the number of α1H channels. This constitutes a novel regulatory mechanism of T-type calcium currents and supports the role of KLHL1 in the modulation of cellular excitability.

Original languageEnglish (US)
Pages (from-to)C1353-C1362
JournalAmerican Journal of Physiology - Cell Physiology
Volume298
Issue number6
DOIs
StatePublished - Jun 1 2010

Keywords

  • Calcium channel
  • Kelch
  • Spinocerebellar ataxia type 8
  • α channel

ASJC Scopus subject areas

  • Physiology
  • Cell Biology

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    Aromolaran, K. A., Benzow, K. A., Cribbs, L. L., Koob, M. D., & Piedras-Rentería, E. S. (2010). T-type current modulation by the actin-binding protein Kelch-like 1. American Journal of Physiology - Cell Physiology, 298(6), C1353-C1362. https://doi.org/10.1152/ajpcell.00235.2009