Smooth muscle contraction is triggered when Ca²⁺/calmodulin-dependent myosin light chain kinase (MLCK) phosphorylates the regulatory light chain of myosin (RLC₂₀). However, blood vessels from Mlck-deficient mouse embryos retain the ability to contract, suggesting the existence of additional regulatory mechanisms. We showed that the p90 ribosomal S6 kinase 2 (RSK2) also phosphorylated RLC₂₀ to promote smooth muscle contractility. Active, phosphorylated RSK2 was present in mouse resistance arteries under normal basal tone, and phosphorylation of RSK2 increased with myogenic vasoconstriction or agonist stimulation. Resistance arteries from Rsk2-deficient mice were dilated and showed reduced myogenic tone and RLC₂₀ phosphorylation. RSK2 phosphorylated Ser¹⁹ in RLC in vitro. In addition, RSK2 phosphorylated an activating site in the Na⁺/H⁺ exchanger (NHE-1), resulting in cytosolic alkalinization and an increase in intracellular Ca²⁺ that promotes vasoconstriction. NHE-1 activity increased upon myogenic constriction, and the increase in intracellular pH was suppressed in Rsk2-deficient mice. In pressured arteries, RSK2-dependent activation of NHE-1 was associated with increased intracellular Ca²⁺ transients, which would be expected to increase MLCK activity, thereby contributing to basal tone and myogenic responses. Accordingly, Rsk2-deficient mice had lower blood pressure than normal littermates. Thus, RSK2 mediates a procontractile signaling pathway that contributes to the regulation of basal vascular tone, myogenic vasoconstriction, and blood pressure and may be a potential therapeutic target in smooth muscle contractility disorders.

当Ca ²⁺ /钙调蛋白依赖性肌球蛋白轻链激酶（MLCK）磷酸化肌球蛋白的调节轻链（RLC ₂₀）时，触发平滑肌收缩。但是，缺乏Mlck的小鼠胚胎的血管保留了收缩的能力，这表明存在其他调控机制。我们显示p90核糖体S6激酶2（RSK2）还磷酸化RLC _20，以促进平滑肌收缩。在正常的基础语调下，活跃的，磷酸化的RSK2存在于小鼠抵抗性动脉中，并且随着肌原性血管收缩或激动剂的刺激，RSK2的磷酸化程度增加。抵抗动脉起Rsk2缺陷小鼠被扩张并显示出降低的肌原性张力和RLC ₂₀磷酸化。RSK2在体外RLC中磷酸化Ser ¹⁹。此外，RSK2磷酸化了Na ⁺ / H ⁺交换子（NHE-1）中的激活位点，导致了胞浆碱化和细胞内Ca ²⁺的增加，从而促进了血管收缩。NHE-1活性在生肌收缩后增加，并且在Rsk2缺陷型小鼠中抑制了细胞内pH的增加。在压力动脉中，NHK-1依赖RSK2的活化与细胞内Ca ^2+的增加有关瞬态现象，有望增加MLCK活性，从而有助于基础音调和肌源性反应。因此，Rsk2缺陷型小鼠的血压低于正常同窝仔。因此，RSK2介导促收缩的信号通路，有助于调节基础血管张力，肌源性血管收缩和血压，并且可能是平滑肌收缩性疾病的潜在治疗靶标。