Down‐regulation of CaV1.2 channels during hypertension: how fewer CaV1.2 channels allow more Ca2+ into hypertensive arterial smooth muscle. (25th November 2013)

• Record Type: Journal Article
• Authors: Tajada, Sendoa; Cidad, Pilar; Colinas, Olaia; Santana, L. Fernando; López‐López, José R.; Pérez‐García, M. Teresa
• Is Part Of: Journal of physiology. Volume 591:Number 24(2013:Dec.)
• Page Start: 6175
• Page End: 6191
• Publication Date: 2013-11-25
• Subjects: Physiology -- Periodicals; 612.005
• DOI: 10.1113/jphysiol.2013.265751
• Languages: English
• ISSNs: 0022-3751

Abstract

<abstract abstract-type="main" xml:lang="en"> <title>Key points</title> <p> <list id="l1" list-type="simple"> <list-item> <label> </label> <p>A hallmark of essential hypertension is an anomalous vascular tone due to the increase in intracellular Ca<sup>2+</sup> ([Ca<sup>2+</sup>]<sub>i</sub>) and/or Ca<sup>2+</sup> sensitivity in vascular smooth muscle. Down‐regulation of K<sup>+</sup> channels together with increased Ca<sub>V</sub>1.2 channel function has been proposed as one pathogenic mechanism.</p> </list-item> <list-item> <label> </label> <p>Using a mouse model of essential hypertension (BPH line), we found a decrease in the global smooth muscle Ca<sup>2+</sup> influx due to fewer Ca<sub>V</sub>1.2 channels. However, these Ca<sub>V</sub>1.2 channels are hyperactive, allowing a larger local Ca<sup>2+</sup> influx at rest that triggers an increased Ca<sup>2+</sup> release from intracellular stores (sparks).</p> </list-item> <list-item> <label> </label> <p>Large conductance, Ca<sup>2+</sup>‐activated K<sup>+</sup> (BK) channels of BPH myocytes show reduced Ca<sup>2+</sup> sensitivity, so that its activation by the increased [Ca<sup>2+</sup>]<sub>i</sub> is impaired.</p> </list-item> <list-item> <label> </label> <p>Our results suggest that changes in the molecular composition of both Ca<sub>V</sub>1.2 and BK channels could explain vascular dysfunction during hypertension in BPH mice.</p> </list-item> </list> </p> <p> <bold>Abstract </bold> Hypertension is a clinical syndrome characterized by increased arterial tone. Although the mechanisms are varied, the generally accepted view is that increased Ca<sub>V</sub>1.2 channel function is a common feature of this pathological condition. Here, we investigated the mechanisms underlying vascular dysfunction in a mouse model of genetic hypertension. Contrary to expectation, we found that whole‐cell Ca<sub>V</sub>1.2 currents (<italic>I</italic><sub>Ca</sub>) were lower in hypertensive (BPH line) than normotensive (BPN line) myocytes. However, local Ca<sub>V</sub>1.2 sparklet activity was higher in BPH cells, suggesting that the relatively low <italic>I</italic><sub>Ca</sub> in these cells was produced by a few hyperactive Ca<sub>V</sub>1.2 channels. Furthermore, our data suggest that while the lower expression of the pore‐forming α<sub>1c</sub> subunit of Ca<sub>V</sub>1.2 currents underlies the lower <italic>I</italic><sub>Ca</sub> in BPH myocytes, the increased sparklet activity was due to a different composition in the auxiliary subunits of the Ca<sub>V</sub>1.2 complexes. <italic>I</italic><sub>Ca</sub> currents in BPN cells were produced by channels composed of α<sub>1c</sub>/α<sub>2</sub>δ/β<sub>3</sub> subunits, while in BPH myocytes currents were probably generated by the opening of channels formed by α<sub>1c</sub>/α<sub>2</sub>δ/β<sub>2</sub> subunits. In addition, Ca<sup>2+</sup> sparks evoked large conductance, Ca<sup>2+</sup>‐activated K<sup>+</sup> (BK) currents of lower magnitude in BPH than in BPN myocytes, because BK channels were less sensitive to Ca<sup>2+</sup>. Our data are consistent with a model in which a decrease in the global number of Ca<sub>V</sub>1.2 currents coexist with the existence of a subpopulation of highly active channels that dominate the resting Ca<sup>2+</sup> influx. The decrease in BK channel activity makes the hyperpolarizing brake ineffective and leads BPH myocytes to a more contracted resting state.</p> </abstract>