The dihydropyridine receptor (DHPR) of skeletal muscle is a voltage dependent L-type Ca2+ channel that controls the entry of Ca2+ into cells to regulate the activity of the channel itself and several Ca2+ dependent signal transduction pathways. The DHPR is also a mechanical gate for the Ca2+ release channel (the ryanodine receptor, RYR1) that regulates release of Ca2+ from intracellular stores to initiate contraction. Physical coupling between the DHPR and RYR1 drives RYR1 activation (orthograde coupling) and prevents L-type channel inactivation (retrograde coupling). We have shown that one site on the L-type channel that interacts with RYR1 is the carboxyterminal tail of the alpha1 subunit. This region of the L-type channel of skeletal and cardiac muscle also binds both Ca2+ and calmodulin (CAM). Ca2+ binding to the bound CaM produces Ca2+ dependent inactivation (CDI) of the channel. Our long range goals are to determine the structure of the DHPR and elucidate the features of the carboxyterminal tails of both the cardiac and skeletal L-type channels that contribute to CDI and E-C coupling.
Our specific aims are to: 1) Determine the structure of the DHPR by cryoelectron microscopy and image reconstruction and map the location of the carboxyterminal tail and the alpha2, beta and gamma subunits in the 3D structure; 2) Elucidate the structure of the carboxyterminal tail of the DHPR alpha1 subunit complexed to CaM; and 3) Evaluate the ability of the carboxyterminal tail of the alpha1 subunit of the DHPR to bind Ca2+ and CaM binding motifs. ? ?
| Halling, D Brent; Georgiou, Dimitra K; Black, D J et al. (2009) Determinants in CaV1 channels that regulate the Ca2+ sensitivity of bound calmodulin. J Biol Chem 284:20041-51 |
| Fallon, Jennifer L; Baker, Mariah R; Xiong, Liangwen et al. (2009) Crystal structure of dimeric cardiac L-type calcium channel regulatory domains bridged by Ca2+* calmodulins. Proc Natl Acad Sci U S A 106:5135-40 |
| Serysheva, Irina I; Ludtke, Steven J; Baker, Matthew L et al. (2008) Subnanometer-resolution electron cryomicroscopy-based domain models for the cytoplasmic region of skeletal muscle RyR channel. Proc Natl Acad Sci U S A 105:9610-5 |
| Serysheva, Irina I; Chiu, Wah; Ludtke, Steven J (2007) Single-particle electron cryomicroscopy of the ion channels in the excitation-contraction coupling junction. Methods Cell Biol 79:407-35 |
| Chelu, Mihail G; Goonasekera, Sanjeewa A; Durham, William J et al. (2006) Heat- and anesthesia-induced malignant hyperthermia in an RyR1 knock-in mouse. FASEB J 20:329-30 |
| Xiong, Liangwen; Zhang, Jia-Zheng; He, Rong et al. (2006) A Ca2+-binding domain in RyR1 that interacts with the calmodulin binding site and modulates channel activity. Biophys J 90:173-82 |
| Black, D J; Halling, D Brent; Mandich, David V et al. (2005) Calmodulin interactions with IQ peptides from voltage-dependent calcium channels. Am J Physiol Cell Physiol 288:C669-76 |
| Ludtke, Steven J; Serysheva, Irina I; Hamilton, Susan L et al. (2005) The pore structure of the closed RyR1 channel. Structure 13:1203-11 |
| Serysheva, Irina I; Hamilton, Susan L; Chiu, Wah et al. (2005) Structure of Ca2+ release channel at 14 A resolution. J Mol Biol 345:427-31 |
| Fallon, Jennifer L; Halling, D Brent; Hamilton, Susan L et al. (2005) Structure of calmodulin bound to the hydrophobic IQ domain of the cardiac Ca(v)1.2 calcium channel. Structure 13:1881-6 |
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