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Multiple determinants in voltage‐dependent P/Q calcium channels control their retention in the endoplasmic reticulum
Author(s) -
Cornet Véronique,
Bichet Delphine,
Sandoz Guillaume,
Marty Isabelle,
Brocard Jacques,
Bourinet Emmanuel,
Mori Yasuo,
Villaz Michel,
De Waard Michel
Publication year - 2002
Publication title -
european journal of neuroscience
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.346
H-Index - 206
eISSN - 1460-9568
pISSN - 0953-816X
DOI - 10.1046/j.1460-9568.2002.02168.x
Subject(s) - endoplasmic reticulum , er retention , protein subunit , r type calcium channel , n type calcium channel , calcium channel , calcium , voltage dependent calcium channel , chemistry , microbiology and biotechnology , biophysics , biology , t type calcium channel , biochemistry , organic chemistry , mutant , gene
Surface expression level of voltage‐dependent calcium channels is tightly controlled in neurons to avoid the resulting cell toxicity generally associated with excessive calcium entry. Cell surface expression of high voltage‐activated calcium channels requires the association of the pore‐forming subunit, Ca v α, with the auxiliary subunit, Ca v β. In the absence of this auxiliary subunit, Ca v α is retained in the endoplasmic reticulum (ER) through mechanisms that are still poorly understood. Here, we have investigated, by a quantitative method based on the use of CD8α chimeras, the molecular determinants of Ca v α 2.1 that are responsible for the retention, in the absence of auxiliary subunits, of P/Q calcium channels in the ER (referred to here as ‘ER retention’). This study demonstrates that the I–II loop of Ca v α 2.1 contains multiple ER‐retention determinants beside the β subunit association domain. In addition, the I–II loop is not the sole domain of calcium channel retention as two regions identified for their ability to interact with the I–II loop, the N‐ and C‐termini of Ca v α 2.1 , also produce ER retention. It is also not an obligatory determinant as, similarly to low‐threshold calcium channels, the I–II loop of Ca v α 1.1 does not produce ER retention in COS7 cells. The data presented here suggests that ER retention is suppressed by sequential molecular events that include: (i) a correct folding of Ca v α in order to mask several internal ER‐retention determinants and (ii) the association of other proteins, including the Ca v β subunit, to suppress the remaining ER‐retention determinants.