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Transient receptor potential vanilloid 4 regulates aquaporin-5 abundance under hypotonic conditions.

ABSTRACT: Aquaporin-5 (AQP5) is expressed in epithelia of lung, cornea, and various secretory glands, sites where extracellular osmolality is known to fluctuate. Hypertonic aquaporin (AQP) induction has been described, but little is known about the effects of a hypotonic environment on AQP abundance. We report that, when mouse lung epithelial cells were exposed to hypotonic medium, a dose-responsive decrease in AQP5 abundance was observed. Hypotonic reduction of AQP5 was blocked by ruthenium red, methanandamide, and miconazole, agents that inhibit the cation channel transient receptor potential vanilloid (TRPV) 4 present in lung epithelial cells. Several observations indicate that TRPV4 participates in hypotonic reduction of AQP5, including a requirement for extracellular calcium to achieve AQP5 reduction; an increase in intracellular calcium in mouse lung epithelial (MLE) cells after hypotonic stimulation; and reduction of AQP5 abundance after addition of the TRPV4 agonist 4alpha-Phorbol-12,13-didecanoate (4alpha-PDD). Similarly, addition of hypotonic PBS to mouse trachea in vivo decreased AQP5 within 1 h, an effect blocked by ruthenium red. To confirm a functional interaction, AQP5 was expressed in control or TRPV4-expressing human embryonic kidney (HEK) cells. Hypotonic reduction of AQP5 was observed only in the presence of TRPV4 and was blocked by ruthenium red. Combined with earlier studies, these observations indicate that AQP5 abundance is tightly regulated along a range of osmolalities and that AQP5 reduction by extracellular hypotonicity can be mediated by TRPV4. These findings have direct relevance to regulation of membrane water permeability and water homeostasis in epithelia of the lung and other organs.

SUBMITTER: Sidhaye VK

PROVIDER: S-EPMC1450241 | biostudies-literature | 2006 Mar

REPOSITORIES: biostudies-literature

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Transient receptor potential vanilloid 4 regulates aquaporin-5 abundance under hypotonic conditions.

Sidhaye Venkataramana K VK Güler Ali D AD Schweitzer Kelly S KS D'Alessio Franco F Caterina Michael J MJ King Landon S LS

Proceedings of the National Academy of Sciences of the United States of America 20060313 12

Aquaporin-5 (AQP5) is expressed in epithelia of lung, cornea, and various secretory glands, sites where extracellular osmolality is known to fluctuate. Hypertonic aquaporin (AQP) induction has been described, but little is known about the effects of a hypotonic environment on AQP abundance. We report that, when mouse lung epithelial cells were exposed to hypotonic medium, a dose-responsive decrease in AQP5 abundance was observed. Hypotonic reduction of AQP5 was blocked by ruthenium red, methanan ...[more]

PMID: 16537379

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Project description:OBJECTIVE:Several physiological stimuli activate smooth muscle cell (SMC) GqPCRs (Gq protein-coupled receptors) to cause vasoconstriction. As a protective mechanism against excessive vasoconstriction, SMC GqPCR stimulation invokes endothelial cell vasodilatory signaling. Whether Ca2+ influx in endothelial cells contributes to the regulation of GqPCR-induced vasoconstriction remains unknown. Ca2+ influx through TRPV4 (transient receptor potential vanilloid 4) channels is a key regulator of endothelium-dependent vasodilation. We hypothesized that SMC GqPCR stimulation engages endothelial TRPV4 channels to limit vasoconstriction. APPROACH AND RESULTS:Using high-speed confocal microscopy to record unitary Ca2+ influx events through TRPV4 channels (TRPV4 sparklets), we report that activation of SMC ?1ARs (alpha1-adrenergic receptors) with phenylephrine or thromboxane A2 receptors with U46619 stimulated TRPV4 sparklets in the native endothelium from mesenteric arteries. Activation of endothelial TRPV4 channels did not require an increase in Ca2+ as indicated by the lack of effect of L-type Ca2+ channel activator or chelator of intracellular Ca2+ EGTA-AM. However, gap junction communication between SMCs and endothelial cells was required for phenylephrine activation or U46619 activation of endothelial TRPV4 channels. Lowering inositol 1,4,5-trisphosphate levels with phospholipase C inhibitor or lithium chloride suppressed phenylephrine activation of endothelial TRPV4 sparklets. Moreover, uncaging inositol 1,4,5-trisphosphate profoundly increased TRPV4 sparklet activity. In pressurized arteries, phenylephrine-induced vasoconstriction was followed by a slow, TRPV4-dependent vasodilation, reflecting activation of negative regulatory mechanism. Consistent with these data, phenylephrine induced a significantly higher increase in blood pressure in TRPV4-/- mice. CONCLUSIONS:These results demonstrate that SMC GqPCR stimulation triggers inositol 1,4,5-trisphosphate-dependent activation of endothelial TRPV4 channels to limit vasoconstriction.

Dataset Information

Transient receptor potential vanilloid 4 regulates aquaporin-5 abundance under hypotonic conditions.

Publications

Transient receptor potential vanilloid 4 regulates aquaporin-5 abundance under hypotonic conditions.

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