AKAP150-dependent cooperative TRPV4 channel gating is central to endothelium-dependent vasodilation and is disrupted in hypertension

Swapnil K. Sonkusare, Thomas Dalsgaard, Adrian D. Bonev, David C. Hill-Eubanks, Michael I. Kotlikoff, John D. Scott, Luis Fernando Santana, Mark T. Nelson

Research output: Contribution to journalArticle

76 Citations (Scopus)

Abstract

Endothelial cell dysfunction, characterized by a diminished response to endothelial cell-dependent vasodilators, is a hallmark of hypertension. TRPV4 channels play a major role in endothelial-dependent vasodilation, a function mediated by local Ca2+influx through clusters of functionally coupled TRPV4 channels rather than by a global increase in endothelial cell Ca2+. We showed that stimulation of muscarinic acetylcholine receptors on endothelial cells of mouse arteries exclusively activated TRPV4 channels that were localized at myoendothelial projections (MEPs), specialized regions of endothelial cells that contact smooth muscle cells. Muscarinic receptor-mediated activation of TRPV4 depended on protein kinase C (PKC) and the PKC-anchoring protein AKAP150, which was concentrated at MEPs. Cooperative opening of clustered TRPV4 channels specifically amplified Ca2+influx at MEPs. Cooperativity of TRPV4 channels at non-MEP sites was much lower, and cooperativity at MEPs was greatly reduced by chelation of intracellular Ca2+or AKAP150 knockout, suggesting that Ca2+entering through adjacent channels underlies the AKAP150-dependent potentiation of TRPV4 activity. In a mouse model of angiotensin II-induced hypertension, MEP localization of AKAP150 was disrupted, muscarinic receptor stimulation did not activate TRPV4 channels, cooperativity among TRPV4 channels at MEPs was weaker, and vasodilation in response to muscarinic receptor stimulation was reduced. Thus, endothelial-dependent dilation of resistance arteries is enabled by MEP-localized AKAP150, which ensures the proximity of PKC to TRPV4 channels and the coupled channel gating necessary for efficient communication from endothelial to smooth muscle cells in arteries. Disruption of this molecular assembly may contribute to altered blood flow in hypertension.

Original languageEnglish (US)
Article numberra66
JournalScience Signaling
Issue number333
DOIs
StatePublished - Jul 8 2014
Externally publishedYes

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Endothelial cells
Vasodilation
Endothelium
Muscarinic Receptors
Endothelial Cells
Hypertension
Protein Kinase C
Arteries
Smooth Muscle Myocytes
Muscle
Cells
Chelation
Vasodilator Agents
Angiotensin II
Dilatation
Blood
Chemical activation
Communication
Proteins

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Sonkusare, S. K., Dalsgaard, T., Bonev, A. D., Hill-Eubanks, D. C., Kotlikoff, M. I., Scott, J. D., ... Nelson, M. T. (2014). AKAP150-dependent cooperative TRPV4 channel gating is central to endothelium-dependent vasodilation and is disrupted in hypertension. Science Signaling, (333), [ra66]. https://doi.org/10.1126/scisignal.2005052

AKAP150-dependent cooperative TRPV4 channel gating is central to endothelium-dependent vasodilation and is disrupted in hypertension. / Sonkusare, Swapnil K.; Dalsgaard, Thomas; Bonev, Adrian D.; Hill-Eubanks, David C.; Kotlikoff, Michael I.; Scott, John D.; Santana, Luis Fernando; Nelson, Mark T.

In: Science Signaling, No. 333, ra66, 08.07.2014.

Research output: Contribution to journalArticle

Sonkusare, Swapnil K. ; Dalsgaard, Thomas ; Bonev, Adrian D. ; Hill-Eubanks, David C. ; Kotlikoff, Michael I. ; Scott, John D. ; Santana, Luis Fernando ; Nelson, Mark T. / AKAP150-dependent cooperative TRPV4 channel gating is central to endothelium-dependent vasodilation and is disrupted in hypertension. In: Science Signaling. 2014 ; No. 333.
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