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Ca 2+ ‐binding proteins tune Ca 2+ ‐feedback to Ca v 1.3 channels in mouse auditory hair cells
Author(s) -
Cui Guiying,
Meyer Alexander C.,
CalinJageman Irina,
Neef Jakob,
Haeseleer Françoise,
Moser Tobias,
Lee Amy
Publication year - 2007
Publication title -
the journal of physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.802
H-Index - 240
eISSN - 1469-7793
pISSN - 0022-3751
DOI - 10.1113/jphysiol.2007.142307
Subject(s) - calmodulin , hair cell , chemistry , biophysics , inner ear , voltage dependent calcium channel , microbiology and biotechnology , calcium , neuroscience , biology , organic chemistry
Sound coding at the auditory inner hair cell synapse requires graded changes in neurotransmitter release, triggered by sustained activation of presynaptic Ca v 1.3 voltage‐gated Ca 2+ channels. Central to their role in this regard, Ca v 1.3 channels in inner hair cells show little Ca 2+ ‐dependent inactivation, a fast negative feedback regulation by incoming Ca 2+ ions, which depends on calmodulin association with the Ca 2+ channel α 1 subunit. Ca 2+ ‐dependent inactivation characterizes nearly all voltage‐gated Ca 2+ channels including Ca v 1.3 in other excitable cells. The mechanism underlying the limited autoregulation of Ca v 1.3 in inner hair cells remains a mystery. Previously, we established calmodulin‐like Ca 2+ ‐binding proteins in the brain and retina (CaBPs) as essential modulators of voltage‐gated Ca 2+ channels. Here, we demonstrate that CaBPs differentially modify Ca 2+ feedback to Ca v 1.3 channels in transfected cells and explore their significance for Ca v 1.3 regulation in inner hair cells. Of multiple CaBPs detected in inner hair cells (CaBP1, CaBP2, CaBP4 and CaBP5), CaBP1 most efficiently blunts Ca 2+ ‐dependent inactivation of Ca v 1.3. CaBP1 and CaBP4 both interact with calmodulin‐binding sequences in Ca v 1.3, but CaBP4 more weakly inhibits Ca 2+ ‐dependent inactivation than CaBP1. Ca 2+ ‐dependent inactivation is marginally greater in inner hair cells from CaBP4 −/− than from wild‐type mice, yet CaBP4 −/− mice are not hearing‐impaired. In contrast to CaBP4, CaBP1 is strongly localized at the presynaptic ribbon synapse of adult inner hair cells both in wild‐type and CaBP4 −/− mice and therefore is positioned to modulate native Ca v 1.3 channels. Our results reveal unexpected diversity in the strengths of CaBPs as Ca 2+ channel modulators, and implicate CaBP1 rather than CaBP4 in conferring the anomalous slow inactivation of Ca v 1.3 Ca 2+ currents required for auditory transmission.