The Perez Group is focused in understanding the molecular mechanisms that control Ca2+ release and Ca2+ homeostasis in striated muscles under normal and myopathic conditions. Our studies primarily concentrate in two major Ca2+ channels (ryanodine receptor-RyRs and dihydropyridine receptor-DHPR) and the role of their endogenous protein modulators in channel function.
Our studies involve the extensive use of unique knockout mice and myogenic cell line null for key Ca2+ regulatory proteins including: RyRs, DHPR 1S and 1a subunits, triadin, junctin and calsequestrin as well as double triadin/junctin null mice. These studies have revealed how different modulators of RyRs regulate its function through specific functional and/or structural interaction. In addition these studies have allowed the identification of the critical molecular determinants of RyRs and DHPR involved in the bidirectional signaling process that takes place during excitation-contract coupling.
In another line of research we are also studying the regulation of RyRs by disease-linked mutations. RyR mutations associated with Ca2+ dysfunction have been linked to several debilitating and deadly myopathies including Malignant Hyperthermia (MH), Central Core Disease, Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT) and Sudden Unexplained Death. Using our RyR-null system we have initiated a comprehensive structural/functional study that focuses on understanding the mechanism by which these mutations affect Ca2+ binding sensitivity and channel activity of the diseased receptors. These studies have revealed a novel calcium-binding site at the core of a mutational hot spot associated with MH and CVPT. This line of research seeks to generate the molecular basis for future development of new therapeutic approaches that target a wide range of myopathies regardless of their etiology. The lab maintains active collaboration with Dr. P.D. Allen, UC. Davis; Dr. Isaac N. Pessah, UC. Davis; Dr. Clara Franzini-Armstrong, University of Pennsylvania; Dr. Montserrat Samso, Virginia Commonwealth University and Dr. Jenny J. Yang, Georgia State University. The group has been supported by American Heart Association is currently funded by NIH.
The lab maintains active collaboration with Dr. P.D. Allen, UC. Davis; Dr. Isaac N. Pessah, UC. Davis; Dr. Clara Franzini-Armstrong, University of Pennsylvania; Dr. Montserrat Samso, Virginia Commonwealth University and Dr. Jenny J. Yang, Georgia State University. The group has been supported by American Heart Association is currently funded by NIH.
- C. F. Perez, Ph.D.
- Siddharth Ramshankar, M.S.
- Pessah I, Lehmler HJ, Robertson L, Perez CF, Cabrales E, Bose D, Feng W (2009) Enantiomeric Specificity of (-)-2,2’,3,3’,6,6’-Hexachlorobiphenyl ((-)-PCB 136) towards ryanodine receptor types 1 and 2. Chem. Res. Toxicol. 22(1):201-207.
- Chopra N, Yang T, Asghari P, Moore ED, Huke S, Akin B, Cattolica RA, Perez CF, Hlaing T, Knollmann-Ritschel BE, Jones LR, Pessah IN, Allen PD, Franzini-Armstrong C, Knollmann BC. (2009) Ablation of triadin causes loss of cardiac Ca2+ release units, impared excitation-contraction coupling and cardiac arrhythmias. Proc. Natl. Acad. Sci. USA 106(18):7636-7641.
- Eltit JM, Wei F, Lopez JR, Padilla IT, Pessah IN, Molinski TF, Fruen BR, Allen PD, Perez CF (2010) Ablation of skeletal muscle triadin impairs FKBP12/RyR1 channel interactions essential for maintaining resting cytoplasmic Ca2+. J Biol Chem. 285(49): 38453-38462.
- Eltit JM, Szpyt J, Li H, Allen PD, Perez CF (2011) Reduced gain of excitation-contraction coupling in triadin-null myotubes is mediated by the disruption of FKBP12/RyR1 interaction. Cell Calcium 49(2):128-135.
- Perez CF (2011) On the footsteps of triadin and its role in skeletal muscle. World J Biol. Chem. 2(8) 177-183.
- Boncompagni S, Thomas M, Lopez JR, Allen PD, Yuan Q, Kranias EG, Franzini-Armstrong C, Perez CF (2012). Triadin/Junctin double null mouse reveals a differential role for Triadin and Junctin in anchoring CASQ to the jSR and regulating Ca2+ homeostasis. PLoS One. 7(7): e39962.
- Szpyt J, Lorenzon N, Perez CF, Norris E, Allen PD, Beam K, Samso M (2012). 3D Localization of the Alpha and Beta Subunits and of the II-III loop in the Skeletal Muscle L-type Ca2+ Channel. J Biol Chem. Nov. 1. PMID: 23118233