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The Journal of Neuroscience, October 18, 2006, 26(42):10677-10689; doi:10.1523/JNEUROSCI.3236-06.2006

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Cellular/Molecular
Switching of Ca²⁺-Dependent Inactivation of Ca_V1.3 Channels by Calcium Binding Proteins of Auditory Hair Cells

Philemon S. Yang,¹ Badr A. Alseikhan,¹ Hakim Hiel,³ Lisa Grant,³ Masayuki X. Mori,¹ Wanjun Yang,¹ Paul A. Fuchs,³ and David T. Yue^1,2

Ca²⁺ Signals Laboratory, Departments of ¹Biomedical Engineering and ²Neuroscience and ³Center for Hearing and Balance, Department of Otolaryngology, Head and Neck Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205

Correspondence should be addressed to David T. Yue, Johns Hopkins University School of Medicine, Departments of Biomedical Engineering and Neuroscience, Calcium Signals Laboratory, Ross 713, 720 Rutland Avenue, Baltimore, MD 21205. Email: dyue{at}bme.jhu.edu

Ca_V1.3 channels comprise a vital subdivision of L-type Ca²⁺ channels: Ca_V1.3 channels mediate neurotransmitter release from auditory inner hair cells (IHCs), pancreatic insulin secretion, and cardiac pacemaking. Fitting with these diverse roles, Ca_V1.3 channels exhibit striking variability in their inactivation by intracellular Ca²⁺. IHCs show generally weak-to-absent Ca²⁺-dependent inactivation (CDI), potentially permitting audition of sustained sounds. In contrast, the strong CDI seen elsewhere likely provides critical negative feedback. Here, we explore this mysterious CDI malleability, particularly its comparative weakness in hair cells. At baseline, heterologously expressed Ca_V1.3 channels exhibit intense CDI, wherein each lobe of calmodulin (CaM) contributes a distinct inactivation component. Because CaM-like molecules (bearing four recognizable but not necessarily functional Ca²⁺-binding EF hands) can perturb the Ca²⁺ response of molecules regulated by CaM, we asked whether such CaM-like entities could influence CDI. We find that CaM-like calcium-binding protein (CaBP) molecules are clearly expressed within the organ of Corti. In particular, the rare subtype CaBP4 is specific to IHCs, and CaBP4 proves capable of eliminating even the potent baseline CDI of Ca_V1.3. CaBP4 thereby represents a plausible candidate for moderating CDI within IHCs.

Key words: FRET two-hybrid; ion-channel modulation; Ca²⁺ signaling; auditory; calmodulin; hair cell

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Received May 17, 2006; revised Aug. 30, 2006; accepted Aug. 31, 2006.

Correspondence should be addressed to David T. Yue, Johns Hopkins University School of Medicine, Departments of Biomedical Engineering and Neuroscience, Calcium Signals Laboratory, Ross 713, 720 Rutland Avenue, Baltimore, MD 21205. Email: dyue{at}bme.jhu.edu

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