Congenital Deafness and Sinoatrial Node Dysfunction in Mice Lacking Class D L-Type Ca2+ Channels

Abstract

Voltage-gated L-type Ca2+ channels (LTCCs) containing a pore-forming alpha1D subunit (D-LTCCs) are expressed in neurons and neuroendocrine cells. Their relative contribution to total L-type Ca2+ currents and their physiological role and significance as a drug target remain unknown. Therefore, we generated D-LTCC deficient mice (alpha1D-/-) that were viable with no major disturbances of glucose metabolism. alpha1D-/-mice were deaf due to the complete absence of L-type currents in cochlear inner hair cells and degeneration of outer and inner hair cells. In wild-type controls, D-LTCC-mediated currents showed low activation thresholds and slow inactivation kinetics. Electrocardiogram recordings revealed sinoatrial node dysfunction (bradycardia and arrhythmia) in alpha1D-/- mice. We conclude that alpha1D can form LTCCs with negative activation thresholds essential for normal auditory function and control of cardiac pacemaker activity.

Gating defects of disease-causing de novo mutations in Cav1.3 Ca2+ channels

“…The only significant change was a small reduction in maximal current amplitude compared to WT in both splice variants. However, based on findings in Ca v 1.3 knockout mice and humans with CACNA1D mutations [19,20], a loss-of-function phenotype by a heterozygous de novo mutation is unlikely to be pathogenic. At present, we cannot rule out the possibility that a special combination of accessory β- and α2δ-subunits, other splice variants or a yet unknown molecular mechanism not active in our expression system can unmask functional changes in M1354I channels.…”

“…Based on findings in Ca v 1.3-deficient mice [19] and humans [20] heterozygous de novo loss-of-function mutations are expected to be clinically silent and only missense mutations with gating changes permitting enhanced Ca 2+ signaling are likely to be disease relevant. However, the functional consequences of such mutations are difficult to predict in silico .…”

Ion Channel Gene Expression in the Inner Ear

“…High voltage-activated channel subunits CACNA1E (Cav1.2, a1C) and CACNA1D (Cav1.3, a1D) (L type) are present in both mouse and rat, while several other subunits such as the intermediate voltage-activated CACNA1E (R-type channel; Cav2.3) were detected only in mouse. The L-type Ca 2+ channel is found in the hair cells of various mammalian and nonmammalian inner ears (Kollmar et al 1997;Ramakrishnan et al 2002;Bao et al 2003;Michna et al 2003;Dou et al 2004;Liang et al 2004;Roche et al 2005), where its loss in the cochlea leads to deafness (Platzer et al 2000). The R-type Ca 2+ channel (CACNA1E, Cav2.3, a1E) was localized to the outer hair cells and their underlying nerves in guinea pig (Green et al 1996;Layton et al 2005), whereas in mouse, it appears in multiple structures during development (e.g., spiral bundle and efferent fibers), but only at the base of the outer hair cells in adult (Waka et al 2003).…”

Mutations in voltage-gated L-type calcium channel: implications in cardiac arrhythmia

“…Ca V 1.3 α 1D ( CACNA1D ) is highly expressed in both SANCs and cochlear inner hair cells [18–21]. Targeted deletion of α 1D caused deafness, pronounced bradycardia, and nonfatal sinoatrial arrhythmia in mice [22,23]. …”

“…The inactivated Ca V 1.3 channels in mice induced strong reduction of calcium current in pacemaker cells and profoundly affected its pacemaking effect, which showed predominant sinoatrial nodal dysfunction [124]. With the inactivated Ca V 1.3 calcium currents, both sinoatrial arrhythmia and bradycardia have been observed [23,125]. A homozygous 3-bp insertion in CACNA1D , inducing p.G403_404ins, was first screened from a Pakistani family with pronounced bradycardia.…”