Claudio F. Perez, PhD

Dr. Claudio F. Perez, PhD, is an Assistant Professor at Harvard Medical School and the leading Investigator of the Laboratory of Molecular Anesthesia and Muscle Physiology. The laboratory focuses on the pathophysiology of skeletal muscle, our research aims at understanding the molecular mechanisms that control calcium metabolism in skeletal and cardiac muscles as well as understand how pathogenic dysregulation of calcium signals leads to myopathies.

Areas of Research

Role of protein-protein interaction in calcium regulation

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 a_1S and b_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 us to identify critical molecular determinants of RyRs and DHPR involved in the bi-directional signaling that takes place during the excitation-contract coupling process.

Structure/Functional coupling between calcium channels

Modulation of RyRs function by the DHPR complex is key to normal muscle function. Dysfunction of the bi-directional cross-talk between these two channels has been associated with several skeletal and cardiac myopathies. Yet the basic mechanism by which DHPR transmit the activation signal to RYRs remains elusive. In our lab we are engaged in a comprehensive analysis of the conformational changes that DHPR undergo during excitation-contraction coupling using state of the art molecular biology approaches and an innovative FRET-based system. These studies are directly correlating conformational changes of the DHPR complex to the structural and functional communication with RyRs. These studies also set the foundations for a broader analysis of the conformational role of a large number of mutations in the DHPR complex that have been directly associated with pathophysiological conditions in heart, muscles and neurons.

Regulation of calcium channels by disease-linked mutations

Many naturally occurring mutations in calcium channels (RyRs and DHPR) lead to dysfunction of calcium homeostasis that 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 myopathies linked to calcium dysregulation.

Selected Publications

1. 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⁺ PLoS One. 7(7): e39962. PMCID: PMC3388061
2. 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⁺ J Biol Chem. 287:43853-43861. PMCID: PMC3527968
3. Chen Y, Xue S, Lopez JR, Yang JJ, Perez CF (2014). Myoplasmic resting Ca²⁺ regulation by RyR is under control of a novel Ca²⁺-binding region of the ryanodine receptor. Biochem J. 460(2):261-71. PMCID: PMC4019983.
4. Altamirano F, Perez CF, Widrick J, Barton ER, Allen PD, Adams JA, López JR (2014). Whole body periodic acceleration (pGz) is an effective therapy to ameliorate muscular dystrophy in mdx PLoS One. 9(9): e106590. PMID: 25181488.
5. Eltit JM, Franzini-Armstrong C, Perez CF (2014). Amino Acid Residues 489-503 of Dihydropyridine Receptor (DHPR) β1a Subunit Are Critical for Structural Communication Between the Skeletal Muscle DHPR complex and Type-1 Ryanodine Receptor. J Biol Chem. 289(52):36116-24. PMID: 25384984
6. Mahalingam M, Perez CF, Fessenden JD (2016). Fluorescence Resonance Energy Transfer-Based Structural Analysis of the Dihydropyridine Receptor a_1S Subunit Reveals Conformational Differences Induced by Binding of the b_1a J Biol. Chem. 291(26):13762-70. PMCID:PMC4919458.
7. Cho CH, Woo JS, Perez CF, Lee EH (2017). A Focus on Extracellular Ca²⁺ Entry into Skeletal Muscle. & Mol. Medicine. 49(9):e378.
8. Perez CF, Eltit JM, Lopez JR, Bodnar D, Dulhunty AF, Aditya S, Casarotto MG (2018). Functional and Structural Characterization of a Novel Malignant Hyperthermia-susceptible variant of DHPR-b_1a subunit (CACNB1). J. Physiol. Cell Physiol. 314(3):C323-C333.

Complete List of Published Work

Bibliography via National Center for Biotechnology Information

Lab Members