Low-voltage-activated T-type calcium channels are essential contributors to the functioning of thalamocortical neurons by supporting burst-firing mode of action potentials. Enhanced T-type calcium conductance has been reported in the Genetic Absence Epilepsy Rat from Strasbourg (GAERS) and proposed to be causally related to the overall development of absence seizure activity. Here, we show that calnexin, an endoplasmic reticulum integral membrane protein, interacts with the III-IV linker region of the Cav3.2 channel to modulate the sorting of the channel to the cell surface. We demonstrate that the GAERS missense mutation located in the Cav3.2 III-IV linker alters the Cav3.2/calnexin interaction, resulting in an increased surface expression of the channel and a concomitant elevation in calcium influx. Our study reveals a novel mechanism that controls the expression of T-type channels, and provides a molecular explanation for the enhancement of T-type calcium conductance in GAERS.

Department of Physiology and Pharmacology Hotchkiss Brain Institute and Alberta Children's Hospital Research Institute Cumming School of Medicine University of Calgary Calgary T2N 4N1 Canada

Institute of Organic Chemistry and Biochemistry Academy of Sciences of the Czech Republic v v i Prague Czech Republic

Michael Smith Laboratories and the Djavad Mowafaghian Centre for Brain Health University of British Columbia Vancouver BC V6T 1Z4 Canada

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The T-type calcium channelosome

Secretory carrier-associated membrane protein 5 regulates cell-surface targeting of T-type calcium channels

Secretory carrier-associated membrane protein 2 (SCAMP2) regulates cell surface expression of T-type calcium channels

A rare CACNA1H variant associated with amyotrophic lateral sclerosis causes complete loss of Cav3.2 T-type channel activity

Genetic T-type calcium channelopathies

Compound heterozygous CACNA1H mutations associated with severe congenital amyotrophy