Down‐regulation of CaV1.2 channels during hypertension: how fewer CaV1.2 channels allow more Ca²⁺ into hypertensive arterial smooth muscle

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