SUMO1 modification of PKD2 channels regulates arterial contractility

Research output: Contribution to journalArticle

Authors

External Institution(s)

  • University of Tennessee Health Science Center

Details

Original languageEnglish (US)
Pages (from-to)27095-27104
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume116
Issue number52
StatusPublished - Dec 26 2019
Peer-reviewedYes

Abstract

PKD2 (polycystin-2, TRPP1) channels are expressed in a wide variety of cell types and can regulate functions, including cell division and contraction. Whether posttranslational modification of PKD2 modifies channel properties is unclear. Similarly uncertain are signaling mechanisms that regulate PKD2 channels in arterial smooth muscle cells (myocytes). Here, by studying inducible, cell-specific Pkd2 knockout mice, we discovered that PKD2 channels are modified by SUMO1 (small ubiquitin-like modifier 1) protein in myocytes of resistance-size arteries. At physiological intravascular pressures, PKD2 exists in approximately equal proportions as either nonsumoylated (PKD2) or triple SUMO1-modifed (SUMO-PKD2) proteins. SUMO-PKD2 recycles,whereas unmodified PKD2 is surfaceresident. Intravascular pressure activates voltage-dependent Ca2+ influx that stimulates the return of internalized SUMO-PKD2 channels to the plasma membrane. In contrast, a reduction in intravascular pressure, membrane hyperpolarization, or inhibition of Ca2+ influx leads to lysosomal degradation of internalized SUMO-PKD2 protein, which reduces surface channel abundance. Through this sumoylation-dependent mechanism, intravascular pressure regulates the surface density of SUMO-PKD2-mediated Na+ currents (INa) in myocytes to control arterial contractility. We also demonstrate that intravascular pressure activates SUMO-PKD2, not PKD2, channels, as desumoylation leads to loss of INa activation in myocytes and vasodilation. In summary, this study reveals that PKD2 channels undergo posttranslational modification by SUMO1, which enables physiological regulation of their surface abundance and pressure-mediated activation in myocytes and thus control of arterial contractility.

    Research areas

  • Arterial smooth muscle, PKD2 channel, Polycystin-2, Sumoylation, Vasoconstriction

Citation formats

APA

Hasan, R., Leo, M. D., Muralidharan, P., Mata-Daboin, A., Yin, W., Bulley, S., ... Jaggar, J. H. (2019). SUMO1 modification of PKD2 channels regulates arterial contractility. Proceedings of the National Academy of Sciences of the United States of America, 116(52), 27095-27104. https://doi.org/10.1073/pnas.1917264116

Harvard

Hasan, R, Leo, MD, Muralidharan, P, Mata-Daboin, A, Yin, W, Bulley, S, Fernandez-Peña, C, MacKay, CE & Jaggar, JH 2019, 'SUMO1 modification of PKD2 channels regulates arterial contractility', Proceedings of the National Academy of Sciences of the United States of America, vol. 116, no. 52, pp. 27095-27104. https://doi.org/10.1073/pnas.1917264116