Ca²⁺‐binding proteins tune Ca²⁺‐feedback to Ca_v1.3 channels in mouse auditory hair cells

Ca 2+ -binding protein 2 inhibits Ca 2+ -channel inactivation in mouse inner hair cells

“…IHC Ca V 1.3 Ca 2+ channels stand out by reason of their hyperpolarized activation range and modest inactivation (10,18,19,22,45). These properties have been attributed to the molecular composition of the native Ca 2+ -channel complexes that, in addition to the specific pore-forming Ca V 1.3α1 splice variant (46), auxiliary Ca V β2 (6,47), and Ca V α 2 δ2 (7) subunit, also contain interactions partners, such as Rab3-interacting molecule (RIM) (48,49); harmonin (50, 51); calmodulin; and, notably, CaBPs (this study and refs.…”

“…Ca 2+ channels at the IHC presynaptic active zone are key signaling elements because they couple the sound-evoked IHC receptor potential to the release of glutamate. IHC Ca 2+ -channel complexes are known to contain Ca V 1.3 α1 subunit (Cav1.3α1) (3-5), betasubunit 2 (Ca V β2) (6), and alpha2-delta subunit 2 (α2δ2) (7) to activate at around −60 mV (8-10), and are partially activated already at the IHC resting potential in vivo [thought to be between −55 and −45 mV (11, 12)], thereby mediating "spontaneous" glutamate release during silence (13).Compared with Ca V 1.3 channels studied in heterologous expression systems, Ca V 1.3 channels in IHCs show little inactivation, which has been attributed to inhibition of calmodulin-mediated Ca 2+ -dependent inactivation (CDI) (14-17) by Ca 2+ -binding proteins (CaBPs) (18,19) and/or the interaction of the distal and proximal regulatory domains of the Ca V 1.3α1 C terminus (20)(21)(22). This "noninactivating" phenotype of IHC Ca V 1.3 enables reliable excitation-secretion coupling during ongoing stimulation (23-25).…”

“…Compared with Ca V 1.3 channels studied in heterologous expression systems, Ca V 1.3 channels in IHCs show little inactivation, which has been attributed to inhibition of calmodulin-mediated Ca 2+ -dependent inactivation (CDI) (14-17) by Ca 2+ -binding proteins (CaBPs) (18,19) and/or the interaction of the distal and proximal regulatory domains of the Ca V 1.3α1 C terminus (20)(21)(22). This "noninactivating" phenotype of IHC Ca V 1.3 enables reliable excitation-secretion coupling during ongoing stimulation (23-25).…”

The Diversity of Calcium Sensor Proteins in the Regulation of Neuronal Function

“…CaBP1-Long and -Short have been found to have roles in the regulation of various Ca 2þ -channels including P/ Q-type (Ca V 2.1) channels (Lee et al 2002), L-type (Ca V 1.2) channels (Zhou et al 2005;Cui et al 2007), TRPC5 channels (KinoshitaKawada et al 2005, and IP 3 Rs (Yang et al 2002), which they apparently inhibit Kasri et al 2004). The interaction of Ca V 2.1 with CaBP1 appears to rely acutely upon amino-terminal myristoylation.…”

Voltage-Gated Calcium Channels

“…The distal carboxy-terminal domain plays an autoregulatory role in both Ca V 1.3 and Ca V 1.4 channels (Singh et al 2006(Singh et al , 2008, but it is not known whether it is subject to proteolytic processing in vivo. Ca V 1.3 channels are regulated by multiple interacting proteins (Cui et al 2007;Jenkins et al 2010), which may be important in tuning their activity to fit the specific requirements of hair cells transmitting auditory information at different frequencies.…”