Abstract
Ca2+-dependent modulation via calmodulin, with consensus CaM-binding IQ motif playing a key role, has been documented for most high-voltage-activated Ca2+ channels. The skeletal muscle Cav1.1 also exhibits Ca2+-/CaM-dependent modulation. Here, whole-cell Ca2+ current, Ca2+ transient, and maximal, immobilization-resistant charge movement (Qmax) recordings were obtained from cultured mouse myotubes, to test a role of IQ motif in function of Cav1.1. The effect of introducing mutation (IQ to AA) of IQ motif into Cav1.1 was examined. In dysgenic myotubes expressing YFP-Cav1.1AA, neither Ca2+ currents nor evoked Ca2+ transients were detectable. The loss of Ca2+ current and excitation-contraction coupling did not appear to be a consequence of defective trafficking to the sarcolemma. The Qmax in dysgenic myotubes expressing YFP-Cav1.1AA was similar to that of normal myotubes. These findings suggest that the IQ motif of the Cav1.1 may be an unrecognized site of structural and functional coupling between DHPR and RyR.
Highlights
Calcium entering the cell through voltage-gated Ca2+ channels plays an important role in mediating a wide variety of cellular events and includes feedback processes that regulate activity of the channel itself
The results indicate that the IQ motif may be a previously unrecognized site of protein-protein interaction between Cav1.1 and the skeletal muscle ryanodine receptor (RyR1) and may play a role in skeletal muscle excitation-contraction (EC) coupling
The data demonstrate in vivo that the IQ motif in the Cterminus of Cav1.1 is critical for function of Cav1.1 as a voltage sensor as well as a Ca2+ channel
Summary
Calcium entering the cell through voltage-gated Ca2+ channels plays an important role in mediating a wide variety of cellular events and includes feedback processes that regulate activity of the channel itself. Ca2+-dependent inactivation (CDI) of Cav1.2 is mediated by CaM, and its structural determinants have been assigned to the proximal region of the C-terminus of Cav1.2 [1, 2]. Three domains have been identified within this region: a Ca2+ binding EF-hand motif, a CaM-tethering site, and a CaM-binding IQ motif. The CaM-tethering site, which consists of both preIQ3 and IQ motifs, resides 50 amino acids downstream from the EF-hand motif and binds Ca2+-free CaM (apo-CaM) at resting [Ca2+]i. The results presented demonstrate that the IQ motif in the C-terminus of Cav1.1 is critical for function of Cav1.1 as a voltage sensor as well as Ca2+ channel. The results indicate that the IQ motif may be a previously unrecognized site of protein-protein interaction between Cav1.1 and the skeletal muscle ryanodine receptor (RyR1) and may play a role in skeletal muscle excitation-contraction (EC) coupling
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