Smooth Muscle Ion Channels and Regulation of Vascular Tone in Resistance Arteries and Arterioles

Abstract

Vascular tone of resistance arteries and arterioles determines peripheral vascular resistance, contributing to the regulation of blood pressure and blood flow to, and within the body's tissues and organs. Ion channels in the plasma membrane and endoplasmic reticulum of vascular smooth muscle cells (SMCs) in these blood vessels importantly contribute to the regulation of intracellular Ca2+ concentration, the primary determinant of SMC contractile activity and vascular tone. Ion channels provide the main source of activator Ca2+ that determines vascular tone, and strongly contribute to setting and regulating membrane potential, which, in turn, regulates the open-state-probability of voltage gated Ca2+ channels (VGCCs), the primary source of Ca2+ in resistance artery and arteriolar SMCs. Ion channel function is also modulated by vasoconstrictors and vasodilators, contributing to all aspects of the regulation of vascular tone. This review will focus on the physiology of VGCCs, voltage-gated K+ (KV) channels, large-conductance Ca2+-activated K+ (BKCa) channels, strong-inward-rectifier K+ (KIR) channels, ATP-sensitive K+ (KATP) channels, ryanodine receptors (RyRs), inositol 1,4,5-trisphosphate receptors (IP3Rs), and a variety of transient receptor potential (TRP) channels that contribute to pressure-induced myogenic tone in resistance arteries and arterioles, the modulation of the function of these ion channels by vasoconstrictors and vasodilators, their role in the functional regulation of tissue blood flow and their dysfunction in diseases such as hypertension, obesity, and diabetes. © 2017 American Physiological Society. Compr Physiol 7:485-581, 2017.

Figure 1

Principal ion channels expressed in vascular SMCs. In the plasma membrane (gray), the following channels are expressed: at least two members of the inward-rectifier K⁺ channel (K_IR) family; large-conductance, Ca²⁺-activated K⁺ channels (K_Ca 1.1); at least six members of the voltage-dependent K⁺ channel (K_v) family; at least two voltage-dependent Ca²⁺ channels (Ca_v); and a number of TRP channels. In the endoplasmic reticular membrane (brown), RyRs and IP₃R are expressed.

Figure 2

Pore-forming subunits of ion channels. All ion channels share a similar topology, wherein the S5 and S6 transmembrane domains (M1 and M2 for K_IR channels) form the ion-permeable pore. These two domains are linked by a pore-loop (P-loop), which contains multiple residues responsible for regulating pore function and ion selectivity. See text for details.

Figure 3

Regulation of Ca_V 1.2 channels by vasoconstrictors and vasodilators. Schematic of the plasma membrane of a vascular SMC showing, from left to right, a Ca_V 1.2 channel, a G_q-protein coupled receptor (G_qPCR), an α5β1 Integrin and a G_s-protein coupled receptor (G_SPCR). Black lines and arrows indicate stimulation, activativation or increases; red lines indicate inhibition. Pathways to the right of the Ca_V 1.2 activate these channels, while those to the left are inhibitory. Membrane depolarization due to opening of membrane channels that conduct Na⁺, Ca²⁺, or Cl⁻ or due to closue of K⁺ channels represents the major stimulus for opening Ca_V 1.2 channels. Vasoconstictor agonists that act through G_qPCRs norepinephrine, endothelin, angiotensin II, 5-HT, etc.) are coupled to phospholipase Cβ (PLCβ), which acts on q membrane phophoinositol bisphosphate to form diacylglycerol (DAG), which, in the presence of Ca²⁺, activates PKC. PKC phosphorylates Ca_V 1.2 to increase its open-state probability. G_qPCR activation can also stimulate phosphatidyl inostitol trisphosphate kinase (PIP₃K), which acts on novel PKCs to activate the tyrosine kinase SRC, as shown. SRC phosphorylates Ca_V 1.2 channels, increasing their activity. Activation of Ca_V 1.2 by PIP₃K independent of PKC and SRC has also been reported. SRC can also be activated by activated inetgrins as shown, also increasing Ca_V 1.2 activity. Agonists for G_sPCR (isoproterenol, adenosine, prostacyclin, CGRP, etc.) activate adenylate cyclase (AC) to increase the formation of cAMP which activates PKA. PKA phosphorylates Ca_V 1.2 to increase the activity of this channel. Membrane hyperpolarization due to opening of K⁺ channels or closure of channels conducting Na⁺, Ca²⁺, or Cl⁻ represents the main stimulus for deactivation of Ca_V 1.2 channels. In addition, nitric oxide (NO) acting through soluble guanylate cyclase (sGC), and other agents that increase cGMP, activate protein kinase G (PKG) which can phosphorylate Ca_V 1.2 channels to decrease their activity. In addition, high levels of cAMP can transactivate PKG accounting for the inhibitory effects of high levels of activation of G_sPCR or direct activators of AC such as forskolin on Ca_V 1.2 channel activity. See text for details and references.

Figure 4

Calcium signaling in feed arteries versus downstream arterioles. Feed arteries display both Ca²⁺ sparks and Ca²⁺ waves, as shown. Ca²⁺ sparks in feed arteries arise from RyRs that may be activated by Ca²⁺ influx through Ca_V 3.2 channels via Ca²⁺-induced Ca²⁺ release. In feed arteries, Ca²⁺ sparks activate BK_Ca channels, hyperpolarizing the membrane and deactivating Ca_V 1.2 channels, which contributes to the negative feedback regulation of myogenic tone. Ca²⁺ waves in feed arteries depend on the activity of both RyRs and IP₃Rs. In arterioles, Ca²⁺ influx through Ca_V 1.2 and other VGCCs provides the Ca²⁺ signal for activation of BK_Ca channels and the negative feedback regulation of membrane potential and VGCC activity. Ca²⁺ waves in arterioles depend solely on the activity of IP₃R. RyRs are expressed in arteriolar SMCs but are silent under resting conditions. See text for details.

Figure 5

Regulation of K_V channels by vasoconstrictors and vasodilators. Schematic of the plasma membrane of a vascular SMC showing, from left to right, a G_q-protein-coupled receptor (G_qPCR), associated G-proteins and phospholipase C-β (PLCβ); a generic K_V channel; and a G_s-protein-coupled receptor, associated G-proteins and adenylate cyclase (AC). Black lines and arrows indicate stimulation, activation or increases; red lines indicate inhibition. Pathways to the right of the K_V channel activate these channels, while those to the left are inhibitory. Membrane depolarization due to opening of membrane channels that conduct Na⁺, Ca²⁺, or Cl⁻ or due to closure of other K⁺ channels represents the major stimulus for opening K_V channels. Vasodilator agonists that act at G_sPCR (isoproterenol, adenosine, prostacyclin, CGRP, etc.), stimulate the formation of cAMP, activation of PKA and phosphorylation of K_V channels leading to their activation. In addition, the G_βγ-subunits can directly interact with some K_V channels also leading to their activation. NO, acting through sGC, and other vasodilators that stimulate the production of cGMP, activeate PKG, phosphorylating K_V channels and increasing their activity. Other vasodilators, such as H₂S and H₂O₂ also can activate K_V channels as shown. Hyperpolarization, induced by opening of other K⁺ channels or closure of channels conducting Na⁺, Ca²⁺, or Cl⁻, represents the major stimulus for closure of K_V channels. In addition, vasoconstrictors that act through Gq-coupled receptors can inhibit K_V channels through several mecahisms including: (A) the activation of PLCβ, the formation of DAG and activation of PKC; (B) PKC-dependent activation of the tyrosine kinase SRC; (C) Rho-guanine-nuclotide exchange factor (Rho-GEF)-dependent activation of RhoA and Rho kinase (Rho K); and (D) agonist-induced increases in intracellular Ca²⁺. See text for more information.

Figure 6

Regulation of BK_Ca channels by vasoconstrictors and vasodilators. Schematic of the plasma membrane of a vascular SMC showing, from left to right, a G_q-protein-coupled receptor (G_qPCR), associated G-proteins and PLCβ; a BK_Ca channel; and a G_s-protein-coupled receptor, associated G-proteins and AC. Black lines and arrows indicate stimulation, activation or increases; red lines indicate inhibition. Pathways to the right of the BK_Ca channel activate these channels, while those to the left are inhibitory. Membrane depolarization due to opening of membrane channels that conduct Na⁺, Ca²⁺, or Cl⁻ or due to closure of other K⁺ channels as well as increases in subsarcolemmal Ca²⁺ are the major stimulae for opening BK_Ca channels. Vasodilator agonists that act at G_sPCR (isoproterenol, adenosine, prostacyclin, CGRP, etc.), stimulate the formation of cAMP, activation of PKA and phosphorylation of BK_Ca channels leading to their activation. Vasodilators that lead to increased production of cAMP als may active BK_Ca channels through exchange EPACs. NO, acting through sGC, and other vasodilators that stimulate the production of cGMP, activate PKG, phosphorylating BK_Ca channels and increasing their activity. Other vasodilators, such as H₂S and H₂O₂ also can activate K_V channels as shown. NO or carbon monoxide (CO) also may directly interact with BK_Ca channels or associated heme-proteins to increase channel activity. BK_Ca channels also are activated by H₂O₂. Conversely, hyperpolarization, induced by opening of other K⁺ channels or closure of channels conducting Na⁺, Ca²⁺, or Cl⁻, and/or a fall in subsarcolemmal Ca²⁺ represent the major stimulae for closure of K_V channels. In addition, vasoconstrictors that act through Gq-coupled receptors can inhibit BK_Ca channels through activation of PLCβ, the formation of diacylglycerol (DAG) and activation of PKC. See text for more information.

Figure 7

Regulation of K_IR channels by vasoconstrictors and vasodilators. Schematic of the plasma membrane of a vascular SMC showing, from left to right, a G_q-protein-coupled receptor (G_qPCR), associated G-proteins and PLCβ; a K_IR channel; and a G_s-protein-coupled receptor, associated G-proteins and AC. Black lines and arrows indicate stimulation, activation or increases; red lines indicate inhibition. Hyperpolarization induced by the activation of other K⁺ channels, or the closure of channels conducting Na⁺, Ca²⁺, or Cl₋ and/or increases in extracellular K⁺ concentration are the major stimuli for activation of vascular SMC K_IR channels. In addition, vasodilators that act at G_sPCRs (isoproterenol, adenosine, prostacyclin, CGRP, etc.), stimulate AC, increase the production of cAMP and activate PKA lead to activation of K_IR channels. Similarly, NO, acting through sGC to increase production of cGMP, activated protein kinase G which can activate K_IR channels. Conversely, membrane depolarization due to closure of other K⁺ channels or opening of channels that conduct Na⁺, Ca²⁺, or Cl₋ will close K_IR channels. Vasoconstrictors that act through G_qPCRs (norepinephrine, endothelin, angiotensin II, 5-HT, etc.) to activate PLCβ, the production of DAG and PKC activation lead to closure of K_IR channels. See text for more information.

Figure 8

Regulation of K_ATP channels by vasoconstrictors and vasodilators. Schematic of the plasma membrane of a vascular SMC showing, from left to right, a G_q-protein-coupled receptor (G_qPCR), associated G-proteins and PLCβ; a K_ATP channel; and a G_s-protein-coupled receptor, associated G-proteins and AC. Black lines and arrows indicate stimulation, activation or increases; red lines indicate inhibition. These channels can be activated by a fall in intracellular ATP in the environment of these channels. In addition, vasodilators that act at G_SPCRs (isoproterenol, adenosine, prostacyclin, CGRP, etc.), stimulate AC, increase the production of cAMP and activate PKA lead to activation of K_ATP channels. Similarly, NO, acting through sGC to increase production of cGMP, activating PKG which can activate K_ATP channels. These channels also can be activated by H₂S, as shown. Conversely, increases in ATP close K_ATP channels. Vasoconstrictors that act through G_qPCRs (norepinephrine, endothelin, angiotensin II, serotonin, etc.) to activate PLCβ, the production of DAG and PKC activation will lead to closure of K_IR channels. Increases in intracellular Ca²⁺ that accompany SMC stimulation by vasoconstrictors activates protein phosphatase 2B (calcineurin), which also closes K_ATP channels by dephosphorylation. See text for more information.

Figure 9

Regulation of RyRs. Schematic of the plasma membrane and the ER membrane of a vascular SMC showing, from left to right in the plasma membrane, a BK_Ca channel and a G_s-protein-coupled receptor, associated G-proteins and AC, and a RyR in the membrane of the ER. Moderate increases in cytoplasmic Ca²⁺ in the environment of a RyR, or increases in the concentration of Ca²⁺ in the lumen of the ER are the primary stimulae for activation of RyRs. Activation of RyR by cytosolic Ca²⁺ is mediated by direct actions of Ca²⁺ on the channels, through activation of calcium-calmodulin-dependent protein kinase (CaMK) and phosphorylation of the channels, or interactions of Ca²⁺ with the Ca²⁺-binding protein S100A which competes with calmodulin for binding to the RyR. Vasodilators that act at G_sPCRs (isoproterenol, adenosine, prostacyclin, CGRP, etc.), activate AC to increase production of cAMP which then can activate PKA to phosphorylate RyRs and increase their activity increasing the frequency of production of Ca²⁺ sparks. Elevated cAMP can also increase RyR activity through activation of EPACs. The increase in RyR-depedent Ca²⁺ spark activity is transduced into membrane hyperpolarization and vasodilation through activation of overlying BK_Ca channels, as shown. Conversely, high levels of intracellular Ca²⁺ inhibit RyR activity through mechanisms involving the Ca²⁺-binding proteins sorcin (SORC) or calmodulin (CaM). The activity of RyRs also may be decreased by interactions with FK-506 binding proteins 12 and 12A FKBPs. See text for more information.

Figure 10

Regulation of IP₃ receptors by vasoconstrictors and vasodilators. Schematic of the plasma membrane and the ER membrane of a vascular SMC showing, from left to right in the plasma membrane, a G_s-protein-coupled receptor, associated G-proteins and AC, a BK_Ca channel, a TRPC3 channel and a G_q-protein-coupled receptor (G_qPCR), associated G-proteins and phospholipase C-β (PLCβ), and an IP₃ receptor (IP₃R) in the membrane of the ER. Increases in IP₃ and moderate increases in cytoplasmic Ca²⁺ in the environment of an IP₃R are the primary stimulae for activation. Activation of IP₃Rs by cytosolic Ca²⁺ is mediated by direct actions of Ca²⁺ on the channels, or through activation of calcium-calmodulin-dependent protein kinase (CaMK) and phosphorylation of the channels. Vasoconstrictors acting through G_qPCRs and activation of PLCβ increase the production of IP₃, stimulating Ca²⁺ release through IP₃R. Activated IP₃Rs have been shown to physically interact with, and activate plasma membrane BK_Ca and TRPC3 channels, as shown. Conversely, high levels of intracellular Ca²⁺ inhibit IP₃R activity through mechanisms involving the Ca²⁺ binding protein, CaM. NO, through activation of soluble guanylate cyclase, increased production of cGMP and activation of PKG phosphorylates IRAG which inhibits IP₃R activity. Vasodilators that act at G_sPCRs (isoproterenol, adenosine, prostacyclin, CGRP, etc.), activate AC to increase producting of cAMP which then can activate PKA to phosphorylate IP₃Rs to decrease their activity. See text for more information.

Figure 11

TRP channel regulation of myogenic and agonist-induced smooth muscle contractility. Increased intravascular pressure activates a stretch-sensitive G_q-protein-coupled-receptor (G_qPCR; e.g., angiotensin type 1 receptor, AT₁R), which then causes the hydrolysis of PIP₂ by phospholipase C- γ1 (PLCγ1) to form DAG and IP₃. DAG activates TRPC6 channels to increase cytosolic Ca²⁺ concentration, combined with IP₃-mediated Ca²⁺ release through IP₃Rs in the ER. This local increase in cytosolic Ca²⁺ concentration activates TRPM4-dependent Na⁺ influx, membrane depolarization, and opening of Ca_v 1.2 channels. This results in SMC contraction (myogenic tone). A similar mechanism is activated in response to a G_qPCR agonist, through activation of PLCβ and TRPC3 channels. Figure adapted, with permission, from Earley and Brayden (361). See text for more information.