Sci Signal. 2014 Jul 8;7(333):ra66. doi: 10.1126/scisignal.2005052.

AKAP150-dependent cooperative TRPV4 channel gating is central to endothelium-dependent vasodilation and is disrupted in hypertension.External 2231691f894ba696de1310221b0a0dbbb31a7251e75115c265587c3d9d5f507c

Sonkusare, S. K., Dalsgaard, T., Bonev, A. D., Hill-Eubanks, D. C., Kotlikoff, M. I., Scott, J. D., Santana, L. F., Nelson, M. T.,
["Department of Pharmacology, College of Medicine, University of Vermont, Burlington, VT 05403, USA.", "Department of Pharmacology, College of Medicine, University of Vermont, Burlington, VT 05403, USA.", "Department of Pharmacology, College of Medicine, University of Vermont, Burlington, VT 05403, USA.", "Department of Pharmacology, College of Medicine, University of Vermont, Burlington, VT 05403, USA.", "Department of Biomedical Sciences, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA.", "Howard Hughes Medical Institute and Department of Pharmacology, University of Washington, Seattle, WA 98195, USA.", "Department of Physiology and Biophysics, University of Washington, Seattle, WA 98195, USA.", "Department of Pharmacology, College of Medicine, University of Vermont, Burlington, VT 05403, USA. Institute of Cardiovascular Sciences, University of Manchester, Manchester M13 9NT, UK. mark.nelson@uvm.edu."]
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 Ca(2+) influx through clusters of functionally coupled TRPV4 channels rather than by a global increase in endothelial cell Ca(2+). 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 Ca(2+) 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 Ca(2+) or AKAP150 knockout, suggesting that Ca(2+) 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.
PMID: 25005230External 2231691f894ba696de1310221b0a0dbbb31a7251e75115c265587c3d9d5f507c
Functional consequence Toggle 893349bafcc528f8346c51dc3420151d67b0126b2c122dd1017121c03fa0f69b
TRP channel Interactor Method Post-translational modification Subcellular trafficking Activity Reference
TRPV4 Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4 AKAP5/AKAP150 Patch clamp Activation 25005230
(Link 2bd4d11adb659cddf58197a94e201f0a44c55d8d7cb427c624971b42e122c0a4: click the arrow icon to show interactions only between the corresponding TRP channel and the interactor)
TRP / Interactor

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