title: Switching of Ca2+-dependent inactivation of Ca(v)1.3 channels by calcium binding proteins of auditory hair cells.
abstract: Ca(V)1.3 channels comprise a vital subdivision of L-type Ca2+ channels: Ca(V)1.3 channels mediate neurotransmitter release from auditory inner hair cells (IHCs), pancreatic insulin secretion, and cardiac pacemaking. Fitting with these diverse roles, Ca(V)1.3 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(V)1.3 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(V)1.3. CaBP4 thereby represents a plausible candidate for moderating CDI within IHCs.
authors.affiliation: Ca2+ Signals Laboratory, Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: Philemon S
authors.initials: PS
authors.lastname: Yang
authors.forename: Badr A
authors.initials: BA
authors.lastname: Alseikhan
authors.forename: Hakim
authors.initials: H
authors.lastname: Hiel
authors.forename: Lisa
authors.initials: L
authors.lastname: Grant
authors.forename: Masayuki X
authors.initials: MX
authors.lastname: Mori
authors.forename: Wanjun
authors.initials: W
authors.lastname: Yang
authors.forename: Paul A
authors.initials: PA
authors.lastname: Fuchs
authors.forename: David T
authors.initials: DT
authors.lastname: Yue
mesh_terms: D000595:Amino Acid Sequence / Q000235:genetics; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D020746:Calcium Channels, L-Type / Q000096:biosynthesis* / Q000235:genetics; D002135:Calcium-Binding Proteins / Q000096:biosynthesis* / Q000235:genetics; D002460:Cell Line; D006199:Hair Cells, Auditory, Inner / Q000378:metabolism*; D006801:Humans; D066298:In Vitro Techniques; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: C472073:CACNA1D protein, human; C494133:Cabp4 protein, mouse; D020746:Calcium Channels, L-Type; D002135:Calcium-Binding Proteins; D009419:Nerve Tissue Proteins; D002118:Calcium