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      Adenosine A 1 receptor signaling inhibits BK channels through a PKCα-dependent mechanism in mouse aortic smooth muscle

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          Adenosine receptors (AR; A 1, A 2A, A 2B, and A 3) contract and relax smooth muscle through different signaling mechanisms. Deciphering these complex responses remains difficult because relationships between AR subtypes and various end-effectors (e.g., enzymes and ion channels) remain to be identified. A 1AR stimulation is associated with the production of 20–hydroxyeicosatetraenoic acid (20–HETE) and activation of protein kinase C (PKC). 20–HETE and PKC can inhibit large conductance Ca 2+/voltage-sensitive K + (BK) channels that regulate smooth muscle contraction. We tested the hypothesis that activation of A 1AR inhibits BK channels via a PKC-dependent mechanism. Patch clamp recordings and Western blots were performed using aortae of wild type (WT) and A 1AR knockout (A 1KO) mice. There were no differences in whole-cell K + current or α and β1 subunits expression between WT and A 1KO. 20–HETE (100 nmol/L) inhibited BK current similarly in WT and A 1KO mice. NECA (5′–N–ethylcarboxamidoadenosine; 10 μmol/L), a nonselective AR agonist, increased BK current in myocytes from both WT and A 1KO mice, but the increase was greater in A 1KO (52 ± 15 vs. 17 ± 3%; P < 0.05). This suggests that A 1AR signaling negatively regulates BK channel activity. Accordingly, CCPA (2–chloro–N(6)-cyclopentyladenosine; 100 nmol/L), an A 1AR-selective agonist, inhibited BK current in myocytes from WT but not A 1KO mice (81 ± 4 vs. 100 ± 7% of control; P < 0.05). Gö6976 (100 nmol/L), a PKCα inhibitor, abolished the effect of CCPA to inhibit BK current (99 ± 3% of control). These data lead us to conclude that, in aortic smooth muscle, A 1AR inhibits BK channel activity and that this occurs via a mechanism involving PKCα.

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          Adenosine receptors as therapeutic targets.

          Adenosine receptors are major targets of caffeine, the most commonly consumed drug in the world. There is growing evidence that they could also be promising therapeutic targets in a wide range of conditions, including cerebral and cardiac ischaemic diseases, sleep disorders, immune and inflammatory disorders and cancer. After more than three decades of medicinal chemistry research, a considerable number of selective agonists and antagonists of adenosine receptors have been discovered, and some have been clinically evaluated, although none has yet received regulatory approval. However, recent advances in the understanding of the roles of the various adenosine receptor subtypes, and in the development of selective and potent ligands, as discussed in this review, have brought the goal of therapeutic application of adenosine receptor modulators considerably closer.
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            Relaxation of arterial smooth muscle by calcium sparks.

            Local increases in intracellular calcium ion concentration ([Ca2+]i) resulting from activation of the ryanodine-sensitive calcium-release channel in the sarcoplasmic reticulum (SR) of smooth muscle cause arterial dilation. Ryanodine-sensitive, spontaneous local increases in [Ca2+]i (Ca2+ sparks) from the SR were observed just under the surface membrane of single smooth muscle cells from myogenic cerebral arteries. Ryanodine and thapsigargin inhibited Ca2+ sparks and Ca(2+)-dependent potassium (KCa) currents, suggesting that Ca2+ sparks activate KCa channels. Furthermore, KCa channels activated by Ca2+ sparks appeared to hyperpolarize and dilate pressurized myogenic arteries because ryanodine and thapsigargin depolarized and constricted these arteries to an extent similar to that produced by blockers of KCa channels. Ca2+ sparks indirectly cause vasodilation through activation of KCa channels, but have little direct effect on spatially averaged [Ca2+]i, which regulates contraction.
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              Physiological roles and properties of potassium channels in arterial smooth muscle.

              This review examines the properties and roles of the four types of K+ channels that have been identified in the cell membrane of arterial smooth muscle cells. 1) Voltage-dependent K+ (KV) channels increase their activity with membrane depolarization and are important regulators of smooth muscle membrane potential in response to depolarizing stimuli. 2) Ca(2+)-activated K+ (KCa) channels respond to changes in intracellular Ca2+ to regulate membrane potential and play an important role in the control of myogenic tone in small arteries. 3) Inward rectifier K+ (KIR) channels regulate membrane potential in smooth muscle cells from several types of resistance arteries and may be responsible for external K(+)-induced dilations. 4) ATP-sensitive K+ (KATP) channels respond to changes in cellular metabolism and are targets of a variety of vasodilating stimuli. The main conclusions of this review are: 1) regulation of arterial smooth muscle membrane potential through activation or inhibition of K+ channel activity provides an important mechanism to dilate or constrict arteries; 2) KV, KCa, KIR, and KATP channels serve unique functions in the regulation of arterial smooth muscle membrane potential; and 3) K+ channels integrate a variety of vasoactive signals to dilate or constrict arteries through regulation of the membrane potential in arterial smooth muscle.

                Author and article information

                Physiol Rep
                Physiol Rep
                Physiological Reports
                Blackwell Publishing Ltd
                August 2013
                29 July 2013
                : 1
                : 3
                [1 ]Department of Physiology and Pharmacology, West Virginia University Morgantown, West Virginia, 26506
                [2 ]Center for Cardiovascular and Respiratory Sciences, West Virginia University Morgantown, West Virginia, 26506
                [3 ]Department of Exercise Physiology, West Virginia University School of Medicine Morgantown, West Virginia, 26506
                Author notes
                S. Jamal Mustafa, Dept of Physiology and Pharmacology, West Virginia University, Morgantown, WV-26506. Tel: 304-293-5830 Fax: 304-293-3850 E-mail: sjmustafa@

                Funding Information This work was supported by National Institutes of Health (NIH) grants HL094447, HL027339 and HL114559.

                © 2013 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of the American Physiological Society and The Physiological Society

                Re-use of this article is permitted in accordance with the Creative Commons Deed, Attribution 2.5, which does not permit commercial exploitation.

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