Delayed Rectifier K+Channels of Vascular Smooth Muscle: Characterization, Function, and Regulation by Phosphorylation

Parathyroid hypertensive factor (PHF) has been implicated in regulation of vascular smooth muscle tone and pathogenesis of several forms of hypertension. Earlier studies have suggested that PHF enhances the actions of other vasoconstrictors, while it has no in vitro vasoconstrictor property of its own. PHF was previously found to enhance the L-type Ca channel currents and intracellular Ca responses to depolarization in vascular smooth muscle cells (VSMCs). The present study examined whether PHF might act on K channels in the plasma membrane of VSMCs. Primary cultured VSMCs from rat tail artery were used. The whole-cell version of the patch-clamp technique was used under conditions in which there was no contribution of Ca-activated K channels to the outward current. Both purified and semipurified PHF inhibited the delayed rectifier type potassium current in a dose-dependent manner. The effect was time dependent and was first significantly different from the control current after 30 min. The inhibition of the delayed rectifier K channel was associated with a time-dependent decrease in the resting membrane potential. Therefore, PHF may alter VSMC cellular Ca responses by reducing the membrane potential to a level closer to the activation potential of Ca channels.Key words: parathyroid hypertensive factor, hypertension, potassium channels, vascular smooth muscle, membrane potential.

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β-Adrenoceptor activation and PKA regulate delayed rectifier K+ channels of vascular smooth muscle cells

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1998.275.2.h448 ◽

1998 ◽

Vol 275 (2) ◽

pp. H448-H459 ◽

Cited By ~ 15

Author(s):

E. Alejandro Aiello ◽

A. Todd Malcolm ◽

Michael P. Walsh ◽

William C. Cole

Keyword(s):

Signal Transduction ◽

Smooth Muscle ◽

Portal Vein ◽

Vascular Smooth Muscle ◽

Smooth Muscle Cells ◽

Vascular Smooth Muscle Cells ◽

Muscle Cells ◽

Catalytic Subunit ◽

Delayed Rectifier ◽

Rabbit Portal Vein

Macroscopic 4-aminopyridine (4-AP)-sensitive, delayed rectifier K+ current of vascular smooth muscle cells is increased during β-adrenoceptor activation with isoproterenol via a signal transduction pathway involving adenylyl cyclase and cAMP-dependent protein kinase (PKA) (Aiello, E. A., M. P. Walsh, and W. C. Cole. Am. J. Physiol. 268 ( Heart Circ. Physiol. 37): H926–H934, 1995.). In this study, we identified the single delayed rectifier K+(KDR) channel(s) of rabbit portal vein myocytes affected by treatment with isoproterenol or the catalytic subunit of PKA. 4-AP-sensitive KDR channels of 15.3 ± 0.6 pS ( n = 5) and 14.8 ± 0.6 pS ( n = 5) conductance, respectively, were observed in inside-out (I-O) and cell-attached (C-A) membrane patches in symmetrical KCl recording conditions. The kinetics of activation (time constant of 10.7 ± 3.02 ms) and inactivation (fast and slow time constants of 0.3 and 2.5 s, respectively) of ensemble currents produced by these channels mimicked those reported for inactivating, 4-AP-sensitive whole cell KDR current of vascular myocytes. Under control conditions, the open probability ( NP o) of KDR channels of C-A membrane patches at −40 mV was 0.014 ± 0.005 ( n = 8). Treatment with 1 μM isoproterenol caused a significant, approximately threefold increase in NP o to 0.041 ± 0.02 ( P < 0.05). KDR channels of I-O patches exhibited rundown after ∼5 min, which was not affected by ATP (5 mM) in the bath solution. Treatment with the purified catalytic subunit of PKA (50 nM; 5 mM ATP) restored KDRchannel activity and caused NP o to increase from 0.011 ± 0.003 to 0.138 ± 0.03 ( P < 0.05; n = 11). These data indicate that small-conductance, 15-pS KDRchannels are responsible for inactivating the macroscopic delayed rectifier K+ current of rabbit portal vein myocytes and that the activity of these channels is enhanced by a signal transduction mechanism involving β-adrenoceptors and phosphorylation by PKA at a membrane potential consistent with that observed in the myocytes in situ.

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Interaction of Carbon Monoxide With K+ Channels in Vascular Smooth Muscle Cells

Signal Transduction and the Gasotransmitters ◽

10.1007/978-1-59259-806-9_11 ◽

2004 ◽

pp. 205-218

Author(s):

Rui Wang

Keyword(s):

Carbon Monoxide ◽

Smooth Muscle ◽

Vascular Smooth Muscle ◽

Smooth Muscle Cells ◽

Vascular Smooth Muscle Cells ◽

Muscle Cells ◽

K Channels

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Involvement of K+ channels in the relaxant effects of YC-1 in vascular smooth muscle

European Journal of Pharmacology ◽

10.1016/s0014-2999(99)00574-9 ◽

1999 ◽

Vol 382 (1) ◽

pp. 11-18 ◽

Cited By ~ 7

Author(s):

Sabine Seitz ◽

Jörg W Wegener ◽

Johanna Rupp ◽

Makino Watanabe ◽

Andreas Jost ◽

...

Keyword(s):

Smooth Muscle ◽

Vascular Smooth Muscle ◽

K Channels

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PERSPECTIVES: Silencing vascular smooth muscle ATP-sensitive K+channels with caveolin-1

The Journal of Physiology ◽

10.1113/jphysiol.2010.196881 ◽

2010 ◽

Vol 588 (17) ◽

pp. 3133-3134

Author(s):

William C. Cole

Keyword(s):

Smooth Muscle ◽

Vascular Smooth Muscle ◽

K Channels ◽

Caveolin 1

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EDHF: an update

Clinical Science ◽

10.1042/cs20090096 ◽

2009 ◽

Vol 117 (4) ◽

pp. 139-155 ◽

Cited By ~ 229

Author(s):

Michel Félétou ◽

Paul M. Vanhoutte

Keyword(s):

Endothelial Cells ◽

Smooth Muscle ◽

Vascular Smooth Muscle ◽

Smooth Muscle Cells ◽

Vascular Smooth Muscle Cells ◽

Electrical Coupling ◽

Muscle Cells ◽

Therapeutic Interventions ◽

K Channels ◽

Acid Metabolites

The endothelium controls vascular tone not only by releasing NO and prostacyclin, but also by other pathways causing hyperpolarization of the underlying smooth muscle cells. This characteristic was at the origin of the term ‘endothelium-derived hyperpolarizing factor’ (EDHF). However, this acronym includes different mechanisms. Arachidonic acid metabolites derived from the cyclo-oxygenases, lipoxygenases and cytochrome P450 pathways, H2O2, CO, H2S and various peptides can be released by endothelial cells. These factors activate different families of K+ channels and hyperpolarization of the vascular smooth muscle cells contribute to the mechanisms leading to their relaxation. Additionally, another pathway associated with the hyperpolarization of both endothelial and vascular smooth muscle cells contributes also to endothelium-dependent relaxations (EDHF-mediated responses). These responses involve an increase in the intracellular Ca2+ concentration of the endothelial cells, followed by the opening of SKCa and IKCa channels (small and intermediate conductance Ca2+-activated K+ channels respectively). These channels have a distinct subcellular distribution: SKCa are widely distributed over the plasma membrane, whereas IKCa are preferentially expressed in the endothelial projections toward the smooth muscle cells. Following SKCa activation, smooth muscle hyperpolarization is preferentially evoked by electrical coupling through myoendothelial gap junctions, whereas, following IKCa activation, K+ efflux can activate smooth muscle Kir2.1 and/or Na+/K+-ATPase. EDHF-mediated responses are altered by aging and various pathologies. Therapeutic interventions can restore these responses, suggesting that the improvement in the EDHF pathway contributes to their beneficial effect. A better characterization of EDHF-mediated responses should allow the determination of whether or not new drugable targets can be identified for the treatment of cardiovascular diseases.

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