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This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 585/3/791    most recent jphysiol.2007.142307v1 Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Cui, G. Articles by Lee, A. Search for Related Content PubMed PubMed Citation Articles by Cui, G. Articles by Lee, A. Related Collections Neuroscience Related Article

¹ Department of Pharmacology and Center for Neurodegenerative Disease, Emory University, Atlanta, GA 30322, USA
² Department of Otolaryngology, Center for Molecular Physiology of the Brain and Bernstein Center for Computational Neuroscience, University of Göttingen, Göttingen, Germany
³ Department of Opthalmology, University of Washington, Seattle, WA 98195, USA

Sound coding at the auditory inner hair cell synapse requires graded changes in neurotransmitter release, triggered by sustained activation of presynaptic Ca_v1.3 voltage-gated Ca²⁺ channels. Central to their role in this regard, Ca_v1.3 channels in inner hair cells show little Ca²⁺-dependent inactivation, a fast negative feedback regulation by incoming Ca²⁺ ions, which depends on calmodulin association with the Ca²⁺ channel ₁ subunit. Ca²⁺-dependent inactivation characterizes nearly all voltage-gated Ca²⁺ channels including Ca_v1.3 in other excitable cells. The mechanism underlying the limited autoregulation of Ca_v1.3 in inner hair cells remains a mystery. Previously, we established calmodulin-like Ca²⁺-binding proteins in the brain and retina (CaBPs) as essential modulators of voltage-gated Ca²⁺ channels. Here, we demonstrate that CaBPs differentially modify Ca²⁺ feedback to Ca_v1.3 channels in transfected cells and explore their significance for Ca_v1.3 regulation in inner hair cells. Of multiple CaBPs detected in inner hair cells (CaBP1, CaBP2, CaBP4 and CaBP5), CaBP1 most efficiently blunts Ca²⁺-dependent inactivation of Ca_v1.3. CaBP1 and CaBP4 both interact with calmodulin-binding sequences in Ca_v1.3, but CaBP4 more weakly inhibits Ca²⁺-dependent inactivation than CaBP1. Ca²⁺-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_v1.3 channels. Our results reveal unexpected diversity in the strengths of CaBPs as Ca²⁺ channel modulators, and implicate CaBP1 rather than CaBP4 in conferring the anomalous slow inactivation of Ca_v1.3 Ca²⁺ currents required for auditory transmission.

(Received 2 August 2007; accepted after revision 15 October 2007; first published online 18 October 2007)
Corresponding author A. Lee: Department of Pharmacology, Emory University School of Medicine, 5123 Rollins Research Bldg, 1510 Clifton Road, Atlanta, GA 30322, USA and T. Moser: InnerEarLab, Department of Otolaryngology, Göttingen University Medical School, Center for Molecular Physiology of the Brain, Bernstein Center for Computational Neurosciences, 37099 Göttingen, Germany. Email: alee{at}pharm.emory.edu and tmoser{at}gwdg.de

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