Contact Information
Department of Neurobiology and Behavior
University of California, Irvine
Irvine, CA 92697-4550
Tel: 949.824.7833
Email:ismith@uci.edu


Calcium is one of the most versatile and universal signaling molecules in the human body and can regulate numerous aspects of cellular function as diverse as fertilization, differentiation, synaptic plasticity and apoptosis. The versatility of calcium as an intracellular messenger depends on its spatial and temporal patterning within the cell. The distribution and colocalisation of calcium binding effector proteins in relation to calcium release channels, as well as the complex properties of these release channels enable calcium signals to exhibit diverse spatial and temporal properties. This further enables spatially restricted 'elementary' signals to provide specificity in cellular response. These elementary calcium events are produced by the opening of a single or a small group of calcium channels located either in the plasma membrane or in the ER, and serve to act as the building blocks of intracellular calcium waves in cells. The functional significance of these microdomains of calcium is highlighted in neurons where different cellular processes, such as transmitter release and activation of enzymes, are regulated by highly localized pulses of calcium. The miniaturization of the neuronal calcium signaling system in this way means that an individual neuron can process and store an enormous amount of information.

Given that calcium regulates so many physiological systems, it is not surprising that disruptions of intracellular calcium homeostasis ('calciumopathies') underlie a host of degenerative disorders. The primary focus of my work is to investigate the generation, interaction and functional consequences of elementary calcium events in neurons to better understand the physiological and pathological functioning of the calcium messenger pathway.

1. Parkinson’s disease (PD) is the most common neurodegenerative movement disorder, involving symptoms including bradykinesia, rigidity and resting tremor. These symptoms are thought to arise from degeneration of dopamine-containing neurons in the substantia nigra pars compacta. In recent years a number of hereditary genes linked to PD have been identified, including mutations in a -synuclein, parkin, PINK1, DJ-1, LRRK2. The precise function of these proteins remains unclear, but they are implicated in mitochondrial functioning and growing evidence suggests that mitochondrial dysfunction is central to PD pathogenesis. A critical role of mitochondria is the buffering of cytosolic Ca 2+ rises; a critical function as Ca 2+ overload leads to neuronal death. Here we are investigating the role of these PD-associated proteins to perturb mitochondrial and cytosolic Ca 2+ homeostasis.

 2. Familial hemiplegic migraine (FHM) is an autosomal dominant classical migraine subtype that typically includes a paralysis of one half of the body during the aura phase. It can be accompanied by other symptoms, such as ataxia, coma and eplileptic seizures.  FHM is caused by missense mutations in the Na, K-ATPase , the neuronal P/Q calcium channel and the neuronal voltage-gated sodium channel. In collaboration with Prof. Jay Gargus at UCI, who has identified and cloned mutations in the α2 gene of the NA,K-ATPase, we are investigating the pathological changes in calcium microdomain homeostasis that underlie the pathogenic changes in global calcium signaling.

3. Elementary calcium signals play an important role in neuronal function and is thought to be involved in the regulation of many physiological processes including, but not limited to, exocytosis, modulation of synaptic strength and control of synaptic structure. Here, we are using membrane-permeant caged compounds to study the mechanisms underlying the generation of calcium waves in primary neurons. A better knowledge of the physiology of elementary calcium signals will aid in the understanding of the pathological process in many disease states.