Local sodium, global reach: filling the gap between salt and hypertension.

The plasma membrane (PM) Na /Ca exchanger (NCX) in vascular smooth muscle is an unique link between the trans-PM Na electrochemical gradient and intracellular Ca and, therefore, between Na ions and Ca signaling, vascular tone and blood pressure. The mechanisms by which Na normally enters the myocytes and influences the Na gradient and NCX activity are, however, incompletely understood. Our view of how Na ions help regulate sarco-/endoplasmic reticulum (S/ER) Ca stores and contractility in arteries has now been signally enhanced by Poburko and colleagues. Using CoroNa green, a Na -sensitive fluorochrome, they observed local Na concentration transient increases (“LNats”) in cultured arterial myocytes. The LNats were generated by Na entry through cation-selective TRPC6 channels, a member of the TRP (transient receptor potential) channel family. This is direct, dynamic evidence for a predicted sub-PM compartment with greatly restricted Na diffusion in which the local rise in Na concentration should drive Ca into the myocytes via NCX. The present study has broad implications for Ca homeostasis and signaling. Earlier vascular smooth muscle studies indicated that other members of the TRP channel family might also admit Na to sub-PM domains. Indirect evidence, as well as an electron microprobe study, indicate that cardiomyocytes, too, can exhibit elevated local sub-PM Na concentrations ([Na ]SPM). Moreover, comparable diffusion-restricted, sub-PM cytosolic compartments may also be present in other types of cells (e.g., astrocytes). To explain how S/ER Ca stores in smooth muscles could refill from the extracellular fluid without inducing contractions,9,10 van Breeman and colleagues postulated a “privileged pathway” (the Ca “buffer barrier”), through which Ca could move directly between the extracellular fluid and the sub-PM (“junctional”) S/ER, jS/ER.9 One mechanism purportedly involved in this Ca transfer was the NCX.9 This model was supported by the discovery that NCX in smooth muscles (and neurons and astrocytes) is confined to PM microdomains that overlie closely-apposed jS/ER,11,12 as are Na pumps with an 2 or 3 catalytic subunit.13–15 In contrast, coexpressed Na pumps with an 1 subunit, the predominant “housekeepers” that maintain the low bulk cytosolic Na concentration ([Na ]CYT), are excluded from these microdomains.13,15 Cation-selective TRPC-containing storeor receptor-operated channels,3,5 which also are located in these PM microdomains,15–17 are, therefore, key Na entry pathways. The jS/ER, the PM microdomains, and the tiny volume of cytosol between them (perhaps 10 19 to 10 18 l), form a structural and functional unit, the “PLasmERosome” (Figure).3 LNats,2 which presumably arise in PLasmERosomes, are surprisingly long-lasting, on the order of 1 minute. Thus, Na diffusion between the PLasmERosomes and bulk cytosol must be markedly restricted. The nature of the diffusion barrier is unknown, but intracellular Na gradients2 could not be sustained even for 1 second if Na diffusivity was comparable to that measured in muscle cytoplasm.18 This helps explain how Na pumps with an 2 or 3 subunit can function in cells that also express 4 times as many pumps with an 1 subunit,19,20 which have a much higher affinity for intracellular Na .21 The implication is that the membrane potential and the balance between Na entry through receptorand store-operated channels, and Na extrusion via the 2/ 3 Na pumps, control [Na ]SPM and the local Na electrochemical gradient. This gradient drives Ca either into or out of the myocytes via NCX, and thereby controls the local sub-PM Ca concentration, [Ca ]SPM. Indeed, [Ca ]SPM transients have been observed in arterial smooth muscle.15,22,23 The [Ca ]SPM, in turn, influences the transport of Ca into the jS/ER (mediated by SERCA pumps), and thereby helps regulate Ca signaling,5,8,17,24 vascular tone and blood pressure.20,24 Mitochondria accumulate Ca when global [Ca ]CYT rises, and mitochondrial NCX may then help the mitochondria extrude Ca . When mitochondrial NCX was inhibited by CGP37157,25 ATP-stimulated global [Na ]CYT rose, as did the frequency of LNats.2 The structural and functional details of the PLasmERosome/SR/mitochondria and bulk cytosol interrelationships are yet to be fully elucidated. The present work advances the concept that local [Na ]SPM controls vascular tone by directly demonstrating local [Na ]SPM, and by identifying a key cation channel that may be involved, TRPC6. Nevertheless, the mechanisms of activation of LNats in arteries may differ from those in cultured cells; different GPCRs (G protein–coupled receptors) and different receptoroperated channels/TRPCs may be involved. It seems unlikely that LNats will be activated by ATP in intact arteries. In the cultured smooth muscle cells used by Poburko,2 ATP (1 mmol/L) activated metabotropic purinergic receptors. But in isolated mouse mesenteric arteries, the effects of bathThe opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association. From the Departments of Physiology (M.P.B., W.G.W.) and Medicine (M.P.B.) and the Center for Heart, Hypertension, and Kidney Disease (M.P.B., W.G.W.), University of Maryland School of Medicine, Baltimore, Md. Correspondence to Mordecai P. Blaustein, MD, Department of Physiology, University of Maryland School of Medicine, 655 W. Baltimore Street, Baltimore, MD 21201. E-mail [email protected] (Circ Res. 2007;101:959-961.) © 2007 American Heart Association, Inc.