My co-workers and I study rapid cellular and subcellular signaling processes mediated by Ca²⁺, protons, IP₃, and other small molecules.  We examine the manner in which these substances control the activation of excitable cardiac and secretory cells and the synaptic transmission between neurons.   Our multifaceted experimental approach builds on electrophysiological, fluorescence-imaging, and molecular techniques.  We aim to describe how the essential properties of cells and tissues may be understood as integrated responses of signaling processes that occur within subcellular micro-domains and organelles (sarcoplasmic reticulum (SR) and mitochondria) and how these processes depend on ionic channels, exchangers, and other signaling proteins that are often arranged in macromolecular complexes.  For this purpose, we use the patch-clamp technique to measure ionic currents at the cellular and single channel levels. We push fluorescence imaging of Ca²⁺ and H⁺ hot-spots towards milli-second and sub-micron resolution by refining confocal and TIRF (total internal reflectance fluorescence) microscopy. Ionic channels and transporters are sequenced, cloned, mutated and expressed in Xenopus oocytes, mammalian cell lines and transgenic animals to elucidate molecular mechanisms and their physiological and pathophysiological consequences.      

Our studies are relevant to the understanding and treatment of cardiac diseases, such as ischemia, arrhythmia, hypertrophy, and cardiomyopathy, and neuro-degenerative conditions, such as Parkinson’s and Alzheimer’s diseases.

A number of current projects are focused on important aspects of cardiac excitation-contraction coupling, such as the multiplicity of Ca²⁺-signaling pathways that serve to fine tune the strength of the heartbeat and the changing importance of these pathways during development and in different parts of the heart.  We have recently discovered a novel Ca²⁺ signaling pathway that is triggered by mechanical shear stress and results in rapid release of Ca²⁺ from mitochondria. Such rapid mitochondrial release is unexpected and it is challenging to explore its sensing mechanism, and how, in sickness and in health, it may act in concert with sarcolemmal Ca²⁺ fluxes and SR Ca²⁺–release processes that are triggered by IP₃- and ryanodine receptors.

Concurrently, we explore the role of mechanical forces/shear-stress/swelling in a study of Cl-channels in cardiac and epithelial cells.

Developmental studies are presently under way to delineate changes in cardiac function that occur from neonatal to postnatal stage where Ca²⁺-signaling is in flux as the cellular ultra-structure and levels of expression of key regulatory proteins undergo rapid changes. This is part of a larger effort to chart important changes in cardiac function that occur during embryonic development, and it is supplemented by studies of differentiation of cardiac cells that are carried out by culturing  pluripotent stem cell lines. 

Our studies of cardiac Ca²⁺-signaling in different species add another dimension to our understanding of cellular specialization. These studies are currently focused on the various roles of the Na⁺-Ca²⁺ exchanger in tissues with and without a functional SR. By developing a transgenic mouse with overexpression of the shark Na⁺-Ca²⁺, we aim to determine how different modes of cAMP-dependent regulation may serve to maintain rapid and complete diastolic relaxation without introducing a potential for arrhythmias.  This transgenic approach has already proven its merits in our previous studies of calsequestrin.    

The effects of acute anoxia are being examined in a study that compares the levels of L-type Ca²⁺ current in the right and left ventricles. We have previously explored such regional differences by comparing Ca²⁺-signaling in atrial and ventricular cells.

Selected Publications:

• Belmonte S, Morad M.  "Pressure-flow"-triggered Cai-transients in rat cardiac myocytes: possible mechanisms and role of mitochondria.  J Physiol. [Epub ahead of print]   2008

• Janowski E, Cleemann L, Sasse P, Morad M.  Diversity of Ca2+ signaling in developing cardiac cells.  Ann N Y Acad Sci.1080:154-64.  2006
• N'Gouemo P, Yasuda RP, Morad M.  Ethanol withdrawal is accompanied by downregulation of calcium channel alpha 1B subunit in rat inferior colliculus neurons. Brain Res. 1108(1):216-20. 2006
• Morad M, Soldatov N: Calcium channel inactivation: possible role in signal transduction and Ca2+ signaling. Cell Calcium. 38:223-231, 2005
• Morad M, Javaheri A, Risius T, Belmonte S: Multimodality of Ca2+ signaling in rat atrial myocytes. Ann N Y Acad Sci. 1047:112-121, 2005
• Woo SH, Cleemann L, Morad M: Diversity of atrial local Ca2+ signalling: evidence from 2-D confocal imaging in Ca2+-buffered rat atrial myocytes. J Physiol. 567:905-921, 2005
• Morad M, Cleemann L, Knollmann BC:  Triadin: the new player on excitation-contraction coupling block.  Circ Res. 96:607-9,  2005
• Abdrakhmanova G, Cleemann L, Lindstrom J, Morad M.Differential modulation of beta2 and beta4 subunits of human neuronal nicotinic acetylcholine receptors by acidification. Mol Pharmacol. 66:347-55, 2004
• Morad M, Chau M. Learning about cardiac calcium signaling from genetic engineering.  Ann N Y Acad Sci. 1015:1-15, 2004
• Woo SH, Soldatov NM, Morad M.  Modulation of Ca2+ signalling in rat atrial myocytes: possible role of the alpha1C carboxyl terminal.  J Physiol. 552:437-47, 2003
• N'Gouemo P, Morad M. Voltage-gated calcium channels in adult rat inferior colliculus neurons. Neurosci. 120:815-826, 2003
• N'Gouemo P, Morad M. Ethanol withdrawal seizure susceptibility is associated with upregulation of L- and P-type Ca2+ channel currents in rat inferior colliculus neurons. Neuropharmacology. 429-437,2003
• He LP, Cleemann L, Soldatov NM, Morad M. Molecular determinants of cAMP-mediated regulation of the Na+-Ca2+ exchanger expressed in human cell lines. J Physiol. 548:677-689, 2003
• Knollmann BC, Kirchhof P, Sirenko SG, Degen H, Greene AE, Schober T, Mackow JC, Fabritz L, Potter JD, Morad M. Familial hypertrophic cardiomyopathy-linked mutant troponin T causes stress-induced ventricular tachycardia and Ca2+-dependent action potential remodeling. Circ Res. 92:428-436, 2003
• Woo SH, Cleemann L, Morad M. Spatiotemporal characteristics of junctional and nonjunctional focal Ca2+ release in rat atrial myocytes. Circ Res. 92:1-11, 2003
• Woo SH, Cleemann L, Morad M. Ca(2+) current-gated focal and local Ca(2+) release in rat atrial myocytes: evidence from rapid 2-D confocal imaging. J Physiol. 543:439-453, 2002
• Abdrakhmanova G, Dorfman J, Xiao Y, Morad M. Protons enhance the gating kinetics of the alpha3/beta4 neuronal nicotinic acetylcholine receptor by increasing its apparent affinity to agonists. Mol Pharmacol. 61:369-378, 2002
• Woo SH, Morad M. Bimodal regulation of Na+-Ca2+ exchanger by beta -adrenergic signaling pathway in shark ventricular myocytes. Proc Natl Acad Sci U S A. 98:2023-2028, 2001
• Knollmann BC, Blatt SA, Horton K, de Freitas F, Miller T, Bell M, Housmans PR, Weissman NJ, Morad M, Potter JD. Inotropic stimulation induces cardiac dysfunction in transgenic mice expressing a troponin T (I79N) mutation linked to familial hypertrophic cardiomyopathy. J Biol Chem. 276:10039-10048, 2001
• Morad M, Suzuki YJ. Redox regulation of cardiac muscle calcium signaling. Antioxid Redox Signal. 2:65-71, 2000
• Soldatov NM, Zhenochin S, AlBanna B, Abernethy DR, Morad M. New molecular determinant for inactivation of the human L-type alpha(1C) Ca(2+) channel. J Membr Biol. 177:129-135, 2000

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