Arterial smooth muscle cell PKD2 (TRPP1) channels regulate systemic blood pressure

Bulley, Simon; Fernández‐Peña, Carlos; Hasan, Raquibul; Leo, M. Dennis; Muralidharan, Padmapriya; Mackay, Charles; Evanson, Kirk W.; Moreira-Júnior, Luiz; Mata-Daboin, Alejandro; Burris, Sarah K; Wang, Qian; Kuruvilla, Korah P.; Jaggar, Jonathan H.

doi:10.7554/elife.42628

Cited by 43 publications

(69 citation statements)

References 46 publications

(72 reference statements)

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“…RT-PCR results confirmed that tamoxifen treatment abolished PKD2 messenger RNA in fresh-isolated arterial myocytes of Pkd2 smKO mice, consistent with a previous report (SI Appendix, Fig. S1) (12). Western blotting revealed that myocyte-specific PKD2 ablation robustly reduced the intensity of 2 protein bands of ∼106 and 140 kDa in arteries ( Fig.…”

Section: Pkd2 Channels Exist As 2 Different Molecular Weight Proteins Insupporting

confidence: 91%

“…Arterial Myocytes. To profile the molecular identity of PKD2 channels in contractile arterial myocytes, we studied resistance-size (≤200 μm diameter) hindlimb arteries of inducible, smooth muscle cell-specific PKD2 knockout (Pkd2 smKO) mice and their controls (Pkd2 fl/fl ) (12). RT-PCR results confirmed that tamoxifen treatment abolished PKD2 messenger RNA in fresh-isolated arterial myocytes of Pkd2 smKO mice, consistent with a previous report (SI Appendix, Fig.…”

Section: Pkd2 Channels Exist As 2 Different Molecular Weight Proteins Insupporting

confidence: 88%

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SUMO1 modification of PKD2 channels regulates arterial contractility

Hasan

Leo

Muralidharan

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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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-specificPkd2knockout 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 surface-resident. 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 INaactivation 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.

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Section: Pkd2 Channels Exist As 2 Different Molecular Weight Proteins Insupporting

confidence: 91%

Section: Pkd2 Channels Exist As 2 Different Molecular Weight Proteins Insupporting

confidence: 88%

SUMO1 modification of PKD2 channels regulates arterial contractility

Hasan

Leo

Muralidharan

et al. 2019

Proc. Natl. Acad. Sci. U.S.A.

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“…Due to its important role in regulating blood pressure, the molecular and biophysical mechanisms underlying this myogenic response have been the subject of intense investigation for decades. This work has led to the formulation of a model in which the myogenic response is initiated when membrane stretch activates Na + -permeable canonical TRPC6, melastatin-type TRPM4, and TRPP1 (PKD2) channels (2)(3)(4). The opening of these channels depolarizes arterial smooth muscle cells, thereby activating voltage-gated, dihydropyridine-sensitive L-type Ca V 1.2 Ca 2+ channels.…”

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confidence: 99%

Kv2.1 channels play opposing roles in regulating membrane potential, Ca ²⁺ channel function, and myogenic tone in arterial smooth muscle

O’Dwyer

Palacio

Matsumoto

et al. 2020

Proc. Natl. Acad. Sci. U.S.A.

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The accepted role of the protein Kv2.1 in arterial smooth muscle cells is to form K + channels in the sarcolemma. Opening of Kv2.1 channels causes membrane hyperpolarization, which decreases the activity of L-type Ca V 1.2 channels, lowering intracellular Ca 2+ ([Ca 2+ ] i ) and causing smooth muscle relaxation. A limitation of this model is that it is based exclusively on data from male arterial myocytes. Here, we used a combination of electrophysiology as well as imaging approaches to investigate the role of Kv2.1 channels in male and female arterial myocytes. We confirmed that Kv2.1 plays a canonical conductive role but found it also has a structural role in arterial myocytes to enhance clustering of Ca V 1.2 channels. Less than 1% of Kv2.1 channels are conductive and induce membrane hyperpolarization. Paradoxically, by enhancing the structural clustering and probability of Ca V 1.2-Ca V 1.2 interactions within these clusters, Kv2.1 increases Ca 2+ influx. These functional impacts of Kv2.1 depend on its level of expression, which varies with sex. In female myocytes, where expression of Kv2.1 protein is higher than in male myocytes, Kv2.1 has conductive and structural roles. Female myocytes have larger Ca V 1.2 clusters, larger [Ca 2+ ] i , and larger myogenic tone than male myocytes. In contrast, in male myocytes, Kv2.1 channels regulate membrane potential but not Ca V 1.2 channel clustering. We propose a model in which Kv2.1 function varies with sex: in males, Kv2.1 channels control membrane potential but, in female myocytes, Kv2.1 plays dual electrical and Ca V 1.2 clustering roles. This contributes to sex-specific regulation of excitability, [Ca 2+ ] i , and myogenic tone in arterial myocytes.

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“…Expression of TRPP channels in vascular smooth muscle contributes to stretch-activated cation currents, which causes vascular smooth muscle membrane depolarization. The activity of these channels has been associated with stretchdependent regulation of vascular tone in cerebral arteries and control of systemic blood pressure [15,16]. The nonselective cation channel TRPC6 is involved in Ca 2+ mobilization leading to vascular smooth muscle contraction [17].…”

Section: Functional Role Of Vascular Smooth Muscle Trp Channelsmentioning

confidence: 99%

Ion Channels and Their Regulation in Vascular Smooth Muscle

Syed¹,

Le²,

Navedo³

et al. 2020

Basic and Clinical Understanding of Microcirculation

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Vascular smooth muscle excitability is exquisitely regulated by different ion channels that control membrane potential (E m) and the magnitude of intracellular calcium inside the cell to induce muscle relaxation or contraction, which significantly influences the microcirculation. Among them, various members of the K + channel family, voltage-gated Ca 2+ channels, and transient receptor potential (TRP) channels are fundamental for control of vascular smooth muscle excitability. These ion channels exist in complex with numerous signaling molecules and binding partners that modulate their function and, in doing so, impact vascular smooth muscle excitability. In this book chapter, we will review our current understanding of some of these ion channels and binding partners in vascular smooth muscle and discuss how their regulation is critical for proper control of (micro)vascular function.

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Arterial smooth muscle cell PKD2 (TRPP1) channels regulate systemic blood pressure

Cited by 43 publications

References 46 publications

SUMO1 modification of PKD2 channels regulates arterial contractility

SUMO1 modification of PKD2 channels regulates arterial contractility

Kv2.1 channels play opposing roles in regulating membrane potential, Ca ²⁺ channel function, and myogenic tone in arterial smooth muscle

Ion Channels and Their Regulation in Vascular Smooth Muscle

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Arterial smooth muscle cell PKD2 (TRPP1) channels regulate systemic blood pressure

Cited by 43 publications

References 46 publications

SUMO1 modification of PKD2 channels regulates arterial contractility

SUMO1 modification of PKD2 channels regulates arterial contractility

Kv2.1 channels play opposing roles in regulating membrane potential, Ca 2+ channel function, and myogenic tone in arterial smooth muscle

Ion Channels and Their Regulation in Vascular Smooth Muscle

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Kv2.1 channels play opposing roles in regulating membrane potential, Ca ²⁺ channel function, and myogenic tone in arterial smooth muscle