From contraction to gene expression： nanojunctions of the sarco/endoplasmic reticulum deliver site- and function-specific calcium signals

Calcium signals determine, for example, smooth muscle contraction and changes in gene expression. How calcium signals se- lect for these processes is enigmatic. We build on the ＂panjunctional sarcoplasmic reticulum＂ hypothesis, describing our view that different calcium pumps and release channels, with different kinetics and affinities for calcium, are strategically positioned within nanojunctions of the SR and help demarcate their respective cytoplasmic nanodomains. SERCA2b and RyR1 are pref- erentially targeted to the sarcoplasmic reticulum （SR） proximal to the plasma membrane （PM）, i.e., to the superficial buffer barrier formed by PM-SR nanojunctions, and support vasodilation. In marked contrast, SERCA2a may be entirely restricted to the deep, perinuclear SR and may supply calcium to this sub-compartment in support of vasoconstriction. RyR3 is also prefer- entially targeted to the perinuclear SR, where its clusters associate with lysosome-SR nanojunctions. The distribution of RyR2 is more widespread and extends from this region to the wider cell. Therefore, perinuclear RyR3s most likely support the initia- tion of global calcium waves at L-SR junctions, which subsequently propagate by calcium-induced calcium release via RyR2 in order to elicit contraction. Data also suggest that unique SERCA and RyR are preferentially targeted to invaginations of the nuclear membrane. Site- and function-specific calcium signals may thus arise to modulate stimulus-response coupling and transcriptional cascades.