Isaac N. Pessah, Ph.D.

Professor, Department of Molecular Biosciences, College of Veterinary Medicine; Director, UC Davis Children’s Center for Environmental Health and Disease Prevention

University of California, Davis Department of Molecular Biosciences
Haring Hall
1278 Surge III
Davis, CA 95616
E-mail:  inpessah@ucdavis.edu

Dr. Pessah is a toxicologist with research interest in the area of molecular and cellular mechanisms regulating signaling in excitable cells.  His current research focuses on the structure, function, and pharmacology of the ryanodine-sensitive calcium channels (RyRs) found in sarcoplasmic and endoplasmic reticulum of muscle cells and neurons. His laboratory is actively studying how dysfunction of RyRs complexes contribute to genetic diseases and how genetic alteration of RyRs and environmental factors interact to influence neurodevelopment by utilizing cellular, biochemical and molecular investigations of calcium-signaling pathways. Dr. Pessah has developed a strong, collaborative and interdisciplinary research program with colleagues across the university. He is a senior member of the NIEHS Center of Excellence in Toxicology and the Superfund Basic Research Program. 

Paolini C, Fessenden JD, Pessah IN, Franzini-Armstrong C. Evidence for conformational coupling between two calcium channels. Proc Natl Acad Sci USA  101: 12748-52, 2004. Ryanodine receptor 1 (RyR1, the sarcoplasmic reticulum Ca2 release channel) and 1Sdihydropyridine receptor (DHPR, the surface membrane voltage sensor) of skeletal muscle belong to separate membrane systems but are functionally and structurally linked. Four 1SDHPRs associated with the four identical subunits of a RyR form a tetrad. We treated skeletal muscle cell lines with ryanodine, at concentrations that block RyRs, and determined whether this treatment affects the distance between DHPRs in the tetrad. We find a substantial ( 2-nm) shift in the  1SDHPR positions, indicating that ryanodine induces large conformational changes in the RyR1 cytoplasmic domain and that the  1SDHPR–RyR complex acts as a unit.

Howard AS, Fitzpatrick R, Pessah I, Kostyniak P, Lein PJ.  Polychlorinated biphenyls induce caspase-dependent cell death in cultured embryonic rat hippocampal but not cortical neurons via activation of the ryanodine receptor. Toxicol Appl Pharmacol 190: 72-86, 2003.
Apoptosis is essential to normal brain development, and perturbation of normal spatiotemporal patterns of apoptosis can cause persistent neural deficits. We tested the hypothesis that PCBs alter apoptosis in neuronal cell types critical to cognitive function. Our results indicate that noncoplanar PCBs induce apoptosis in hippocampal neurons subsequent to ryanodine receptor activation and increased reactive oxygen species and suggest that altered regional profiles of apoptosis may be an important mechanism underlying the developmental neurotoxicity of PCBs.

Voss AA, Lango J, Ernst-Russell M, Morin D, Pessah IN. Identification of Hyperreactive Cysteines within Ryanodine Receptor Type 1 by Mass Spectrometry. J Biol Chem June 14, 2004 (Epub ahead of print).  Reports the exact identity of the hyper-reactive cysteines involved in redox modulation of ryanodine receptors, a major target of thimerosal.  This basic knowledge will help us understand how these channel complexes respond to local changes in redox potential and how thimerosal alters this important function.

Gronert GA, Pessah IN, Muldoon SM, Tautz TJ. Malignant Hyperthermia.  In Anesthesia, 6th Edition, RD Miller, ed., Churchill Livingstone, Phil. PA, pp1033-1052, 2004. A major book chapter reviewing the molecular, cellular, and clinical basis of a pharmacogenic disease called malignant.hyperthermia.

Cherednichenko G, Zema AV, Schaefer S, Feng W, Blatter LA, Pessah IN. NADH oxidase activity of rat cardiac sarcoplasmic reticulum regulates calcium-induced calcium release. Circ Res 94, 478-486, 2004.  Reports an enzyme activity closely associated with the EC coupling machinery in cardiac muscle cells and essential for proper redox modulation of ryanodine receptors, a major target of thimerosal.  Basic knowledge of this type will help us understand how these channel complexes respond to local changes in redox potential and changing metabolic state and how thimerosal alters this important function.

Gafni J, Wong PW, Pessah IN. Noncoplanar 2,2,3,5,6-pentachlorobiphenyl (PCB 95) and rapamycin amplify ryanodine receptor signaling and Ca2+ entry mediated by ionotrophic glutamate receptors in cerebellar granule neurons. Toxicol Sci 77, 72-82, 2004. Paper reports that non-coplanar PCBs (those that predominate in human and environmental samples) enhance excitatory neurotransmitter responses in granule neurons isolated from the cerebellum. This is the first study to show that the excitatory neurotoxicity of PCBs is depends on functional contexts.

Yang T, Ta TA, Pessah IN, Allen PD. Functional defects in six RyR1 mutations associated with malignant hyperthermia and their impact on skeletal E-C coupling J. Biol. Chem. 278, 25722-30, 2003. Using a homologous expression system, this study demonstrates for the first time that these 7 MH mutations are all both necessary and sufficient to induce MH-related phenotypes. Decreased sensitivity to calcium and magnesium, inhibition and inability of MHRyR1s to be fully inactivated at [Ca2]i typical of normal myotubes at rest are key defects that contribute to the initiation of MH episodes.

Focus on Autism Research: Genetics of Autism, UCLA Psychiatry Grand Rounds & Rhoda and Bernard G. Sarnat Endowed Lecturer, Los Angeles, CA, April 2004.

Principal Investigator/ Director: Center for Children’s Environmental Health and Disease Prevention: Environmental Factors in the Etiology of Autism, NIEHS/ EPA, 9/01-8/06, $1,000,000 annual direct.  To establish a multidisciplinary Center that examines the influence of environmental xenobiotics on the incidence and severity of childhood autism.

Principal Investigator:  E-C Coupling: Signaling Between Calcium Channels (Project 4), NIH, 9/02-8/07, $158,537 annual direct.  To understand how RyR and plasmalemmal calcium channels communicate and regulate EC coupling.

Co-Principal Investigator (PI: P.D. Allen): Genetic and Environmental Factors influencing MH Susceptibility, NIH, 12/99-11/04, $132,242 annual direct. To create transgenic mice carrying the major human mutations for MH and determine how environmental factors influence the phenotypic penetrance of these mutations.

Co-Principal Investigator (PI: P.D. Allen): Structure Function Studies of RyR1 in a Myogenic Knockout, 4/01-3/06, $139,863 annual direct.  The goals of this project are to create a transgenic muscle cell line that  is null for any known RyR complex. Homologous expression of wildtype and mutated RyR cDNAs is used to study the molecular details of how RyR structure relates to function.

M.I.N.D. Institute, Group Leader- Models of Neurodevelopmental Toxicity
Federal Insecticide, Fungicide and Rodenticide Act (FIFRA)- Science Advisory Board
National Institute of Environmental Health Sciences- Ad Hoc Study Section
Department of Biochemistry and Molecular Medicine- Membership Committee
Pharmacology and Toxicology Graduate Group- Graduate Group Chair, and Member Committee on Educational Policy
Department of Molecular Biosciences Recruitment Committee
Department of Anatomy, Physiology and Cell Biology- Recruitment Committee
Editorial Board: Neurotoxicology and Teratology, Environmental Pharmacology and Toxicology
Reviewer: Journal of Biochemistry, Journal of Neurochemistry, Biophysical Journal, American Journal of Cell Physiology, Circulation Research, Neurotoxicology and Teratology, Environmental Pharmacology and Toxicology, Toxicological Sciences, Life Sciences

Pfizer Research Award for Excellence