Nanojunctions of the Sarcoplasmic Reticulum Deliver Site- and Function-specific Calcium Signalling in Vascular Smooth Muscles

Vasoactive agents may induce blood vessel constriction or dilation by eliciting calcium signals within vascular smooth muscles. It is also evident that calcium signals coordinate the switch from a contractile to a migratory-proliferative smooth muscle phenotype(s), which requires changes in gene expression. However, as yet we have little understanding of the mechanisms by which different calcium signals are generated in order to select for each, sometimes opposing, function. To this end we have proposed that the strategic positioning of calcium pumps and release channels at membrane-membrane nanojunctions of the sarcoplasmic reticulum (SR) demarcates cytoplasmic nanodomains, within which site- and function-specific calcium signals arise. The present project will explore how nanojunctions of the sarcoplasmic reticulum may: (1) define cytoplasmic nanospaces about the plasma membrane, mitochondria, contractile myofilaments, lysosomes and the nucleus; (2) Provide for functional segregation by restricting passive diffusion and by coordinating active ion transfer within a given nanospace via resident calcium pumps and release channels; (3) Select for contraction, relaxation and / or changes in gene expression; (4) Facilitate the switch in myocyte phenotype through junctional reorganisation. Consideration of these aims alone highlights the need for further exploration of cellular nanojunctions and the mechanisms by which they operate, and such studies will undoubtedly open up new therapeutic horizons. You will utilize immunofluoresence teachniques, molecular biology, confocal imaging and electrophysiology to explore the structural architecture of nanojunctions formed by the sarcoplasmic reticulum, the molecular machinery they hold and the mechanisms by they deliver site- and function-specific calcium signals.