Microdomains and Organized Signaling in Regulating Kv Channel Function in PASMC

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An emerging idea in signal transduction posits the existence of spatially organized complexes of signaling molecules in microdomains (62, 65) of the plasma membrane. Recent studies have focused on the distribution of signaling molecules in caveolae, which are cholesterol and sphingolipid-enriched regions that can form distinct structural invaginations of the plasma membrane and are enriched of the protein caveolin (97). This notion of signaling microdomains is attractive in that it would account for a localization of receptors, signaling components, and effector molecules (e.g., ion channels) in a confined region to facilitate coordinated, precise, and rapid regulation of cell function.

Knock-out mice deficient in caveolin-1 protein, required in the structural formation of caveolae, phenotypically expresses pulmonary hypertension with marked right ventricular hypertrophy and appear to have unregulated NO generation (128). This suggests that the formation of caveolae is integral to the pulmonary vasculature and that stress such as chronic hypoxia may lead to malformation or lack ofessential caveolae components. As this is done in a small rodent model, possible implication of caveolae in larger mammals may be different and it is debatable whether pulmonary hypertension is a manifestation of too little or too many caveolae in humans. Equally compelling and rational arguments can be made for both possibilities.

Though caveolae from cardiomyocytes have been show to be enriched in adrenergic receptors, adenylyl cyclase, and related signaling machinery, not much data exists for signaling complexes assembled in animal or human PASMC. It is likely that similar enrichment exists in PASMC, but it is equally likely that, because these cells contain machinery to respond to low Po2, there may be enrichment of a) oxygen sensor(s) such as NADPH-P-450 oxidoreductase complex and/or a heme- and metal-containing motif; b) couplers (e.g., ODCR), signal transduction proteins, and/or modulators (e.g., KChAP, KChIP), and c) effectors such as Kv channels (e.g., Kvl.5) and Ca2+ channels (e.g., VDCC) in caveolae allowing for localized sensing and rapid response to modulate cell physiology (Fig. 9). It has been demonstrated that Kv1.5 specifically targets to caveolae, whereas depletion of cellular cholesterol and inhibition of sphingolipid synthesis alter Kv1.5 channel function (50).

It is possible that caveolae may contribute to regulation of Kv channels during acute and chronic hypoxia. Lipid rafts, of which caveolae are a subclass, are enriched in arachidonic acid (AA) and stresses (e.g., ischemia) can release AA (77, 87). Recent studies involving brain hypoxia (7) and heart ischemia (71) reveal through gene array analysis that a common response is the activation of 12-lipoxygenase, an enzyme that metabolizes AA and generates biologically-active metabolites. Other AA metabolizing enzymes are also induced and their tissue specific expression determines cellular responses to hypoxia. Epoxyeicosatrienoic acids (EETs) are cytochrome P450-derived AA metabolite and have the ability to regulate vascular tone. Though most EETs cause vasodilation through activation of K+ channels, 14,15-EET activates Ca2+ channels and cause Ca2+ influx and induce vasoconstriction (24). Therefore, it is likely that there exists a delicate balance in PASMC between numerous factors that cause relaxation and contraction by modulating Kv channel activity, of which AA metabolites may be a particular regulatory component that can be easily exploited by hypoxia through closing of Kv channels and opening of Ca2+ channels. This would suggest that caveolae and their localized components contribute to the development of hypoxia-mediated Kv channel inhibition, pulmonary vasoconstriction, vascular remodeling, and pulmonary hypertension. Caveolae may thus serve as an organizing center for cellular signaling and the particular responses elicited by hypoxia may be a manifestation of the enriched signaling components in caveolae dependent on the remodeled state of the pulmonary vasculature.

Figure 9. Schematic representation of the organization of ion channels, membrane receptors, and signal transduction proteins in a caveolae. Kv channels within the caveolae are modulated by protein kinase A (PKA), Ca2+ (from the SR and extracellular site), mitochondrial cyt-c and superoxide, EETs/HETEs, and NADPH oxidase-produced superoxide. NADPH oxidase is depicted as a multi-subunit enzyme complex comprised of gp91, gp22, p47, p67, p40, and rac proteins. AC, adenylate cyclase; EETs, epoxyeicosatrienoic acids; HETEs, hydroxyeicosatetraenoic acids, P, phosphorylation sites, KChIP, K+ channel interacting protein; KChAP, K+ channel associated proteins; ROS, reactive oxygen species.

Figure 9. Schematic representation of the organization of ion channels, membrane receptors, and signal transduction proteins in a caveolae. Kv channels within the caveolae are modulated by protein kinase A (PKA), Ca2+ (from the SR and extracellular site), mitochondrial cyt-c and superoxide, EETs/HETEs, and NADPH oxidase-produced superoxide. NADPH oxidase is depicted as a multi-subunit enzyme complex comprised of gp91, gp22, p47, p67, p40, and rac proteins. AC, adenylate cyclase; EETs, epoxyeicosatrienoic acids; HETEs, hydroxyeicosatetraenoic acids, P, phosphorylation sites, KChIP, K+ channel interacting protein; KChAP, K+ channel associated proteins; ROS, reactive oxygen species.

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