The central importance of calcium clearance proteins, and their regulators, in the modulation of myocardial contractility and intracellular Ca 2+ concentration ([Ca 2+ ] i ) has long been established. Key players identified include the Na + -Ca 2+ exchanger, the Na + -K + ATPase, the sarco(endo)plasmic reticulum Ca 2+ -ATPase and associated phospholamban. Gene-targeted and transgenic murine models have been critical in the elucidation of their function. The study of these proteins in the regulation of contractile parameters in vascular smooth muscle, on the other hand, is less well studied. More recently, gene-targeted and transgenic models have expanded our knowledge of Ca 2+ clearance proteins and their role in both tonic and phasic smooth muscle contractility. In this review, we will briefly treat the mechanisms which underlie Ca 2+ clearance in smooth muscle. These will be addressed in light of studies using gene-modified mouse models, the results of which will be compared and contrasted with those in the cardiomyocyte. The recently identified human mutations in phospholamban, which lead to dilated cardiomyopathy, are also present in vascular and other smooth muscle. Given the importance of these Ca 2+ clearance systems to modulation of smooth muscle, it is likely that mutations will also lead to smooth muscle pathology.
Ca 2+ CLEARANCE AND REGULATION OF [Ca 2+ ] iCa 2+ homeostasis is central to the regulation of smooth muscle function. It is well established that [Ca 2+ ] i plays an essential role in the activation of myosin light chain kinase, which phosphorylates myosin, thereby activating the actin-myosin interaction (for review see [1]). It has also be estimated that Ca 2+ influx under basal conditions is 16 μmole/liter per minute, more than 2 orders of magnitude greater than the resting [Ca 2+ ] i . Thus Ca 2+ clearance from the cytosol is critical to the maintenance of a quiescent baseline and is a major factor in modulation of Ca 2+ homeostasis and thus contractile force. The plasma membrane Ca 2+ ATPase (PMCA), sarco(endo)plasmic reticulum Ca 2+ -ATPase (SERCA), Na + -Ca 2+ -exchanger (NCX) and mitochondria all function to some extent in this process (for reviews see [2,3]). Figure 1 shows a schematic illustration of these Ca 2+ clearance pathways. Also of importance to smooth muscle Ca 2+ clearance are phospholamban (PLN), an endogenous inhibitor of SERCA, and the Na + -K + ATPase (NKA), which couples to NCX, and facilitates the extrusion of Ca 2+ via the forward mode of the exchanger. NCX is generally considered to be a high-capacity exchanger, i.e., low affinity for Ca 2+ (K d ≈1 μM), but high turnover [4][5][6][7]. SERCA and PMCA, on the other hand, have a higher affinity for Ca 2+ (K d ≈0.1-0.3 μM) [6,[8][9][10][11], but lower turnover than NCX. For smooth muscle, the relative contribution of each to Ca 2+ clearance is dependent on conditions and smooth muscle type, but in general, NCX accounts for about 60%, while PMCA and Publisher's Disclaimer: This is a PDF file of an unedited manu...
