Tissue specificity the role of nanospaces between the organellar membranes in smooth muscle Ca2+ signaling

Abstract

In this chapter we examine the importance of cytoplasmic nanospaces-nanometer scale spaces between organellar membranes-to the cell signaling machinery, with specific reference to Ca2+ transport and signaling in smooth muscle cells. More specifically, we will consider the extent to which quantitative modeling may aid in the development of our understanding of these processes. Testament to the requirement for such approaches lies in the fact that recent studies have provided evermore convincing evidence in support of the view that cytoplasmic nanospaces may be as significant to the process of Ca2+ signaling as the Ca2+ transporters, release channels and Ca2+ storing organelles themselves. Moreover, the disruption and/or dysfunction of cytoplasmic nanospaces may be central to the origin of certain diseases. By way of introduction, we provide a historical perspective on the identification of smooth muscle cell plasma membrane (PM)-sarcoplasmic reticulum (SR) nanospaces, and the early evidence in support of their role in the generation of asynchronous Ca2+ waves. We then summarize how stochastic modeling approaches can aid and guide the development of our understanding of two basic functional steps leading to healthy smooth muscle cell contraction. We furthermore outline how more sophisticated and realistic quantitative stochastic modeling may be employed to not only test, but to lead in the development of working hypotheses in a manner that informs further experimental investigation. Finally, we consider more recently defined nanospaces such as, for example, the lysosome-SR junction, by way of demonstrating the importance of quantitative stochastic modeling to our understanding of signaling mechanisms.