Pulmonary arterial hypertension is driven by smooth muscle contraction and by the switch from a contractile to a migratory-proliferative smooth muscle phenotype(s), which requires changes in gene expression. These processes are selected, in part, by calcium signals, but how different calcium signals are generated to select each function is enigmatic. We have previously shown that SERCA2b and RyR1 are preferentially targeted to the sarcoplasmic reticulum (SR) proximal to the plasma membrane (PM) in pulmonary arterial smooth muscle cells (PASMCs; Clark et al., 2010); i.e. to the superficial buffer barrier formed by PM-SR nanojunctions (van Breemen et al., 2013). Here they may support vasodilation in response to β-adrenoceptor activation. Induced increases in SERCA2b activity may thus remove calcium from the deeper cytoplasm to the superficial SR, from which calcium sparks may be released into the PM-SR junction via RyR1 to activate PM resident BKCa channels, driving hyperpolarisation (Boittin et al., 2003), removal of calcium from the cell by forward mode NCX activity and ultimately vasodilation (Boittin et al., 2003; Clark et al., 2010). In marked contrast, SERCA2a is entirely restricted to the deep, perinuclear SR (Clark et al., 2010) and may function to recycle calcium into this sub-compartment in support of vasoconstriction (Dipp & Evans, 2001; Dipp et al., 2001; Kinnear et al., 2004; Clark et al., 2010). Importantly, differrent subtypes of RyR are also strategically positioned here. RyR3 is preferentially targeted to the perinuclear SR and associated lysosome-SR nanojunctions (Kinnear et al., 2004, Kinnear et al., 2008), while the distribution of RyR2 is more widespread and extends from this region to the wider cell (Kinnear et al., 2008; Clark et al., 2010). We therefore proposed that perinuclear clusters of RyR3 may act as an initiation site for propagating calcium waves and contraction (Dipp & Evans, 2001; Kinnear et al., 2008). Thereafter, by calcium-induced calcium release, RyR2 may carry propagating calcium waves away from perinuclear clusters of RyR3 and across the myofilaments to enhance myocyte contraction (Kinnear et al., 2008; Clark et al., 2010). We have now identified a third subtype of SERCA pump in PASMCs, namely SERCA1, which together with RyR1 preferentially lines the nucleoplasmic reticulum (nSR). By contrast, we find no evidence of similar nSR labeling for other SERCA or RyR. It seems likely, therefore, that a variety of calcium pumps and release channels, with different kinetics and affinities for calcium, are strategically positioned within and serve to demarcate different nanojunctions of the SR and their respective cytoplasmic nanodomains. Function-specific calcium signals may thus arise to provide for selective modulation of smooth muscle contraction and gene expression.