Trevor J. Shuttleworth, Ph.D.

The cellular actions of many neurotransmitters and hormones are dependent on receptor-activated increases in intracellular calcium concentrations in their target cells. In various secretory and other "non-excitable" cells, the physiologically relevant signals often take the form of a series of Ca2+ oscillations, and many critical cellular responses are tuned to respond to the specific frequency of such oscillations. A key factor in sustaining these signals and determining their frequency, is the receptor-activated entry of Ca2+ from the extracellular medium. Our research concerns the nature of the conductances responsible for this entry, and their specific roles in modulating the overall Ca2+ signal. Specifically, our recent research has focused on the ARC channel – a novel Ca2+ entry channel that is activated by the receptor-mediated generation of arachidonic acid, and which we first described a few years ago. Importantly, it is this channel that appears to play the major role in the entry of Ca2+ during the generation of the oscillatory Ca2+ signals in several cell types. We have recently characterized the key molecular components of this channel, revealing that it is a member of a new family of channels – the "Orai-based channels". This molecular characterization has opened up new opportunities for the analysis of its nature, mechanism of activation, and regulation. This, along with identifying how the Ca2+ entering via this channel acts to modulate the frequency of the agonist-induced Ca2+ oscillations, forms the major focus of our current research.

Techniques used include patch-clamp analysis of ion-channel activity, digital imaging, real-time confocal imaging, and photon-counting microfluorimetric measurements of intracellular Ca2+ concentrations in single cells, and biochemical and molecular studies of the proteins that form the channel and its regulators.