alpha2C Adrenergic Receptors & Cutaneous Circulation

描述(申请人提供)：在冷暴露期间，皮肤血流量减少，以防止热量损失。这是通过增加交感神经张力和寒冷诱导的皮肤动脉对去甲肾上腺素收缩的敏感性来调节的。后一种作用是由冷诱导的(α2-肾上腺素能受体(α2-AR)功能的放大所介导的。虽然α2-Ars包括3个亚型，但只有Alpha2C-Ars对冷有反应。虽然α2C-AR在37℃时不起作用，但它们完全负责冷诱导的α2-AR收缩的扩增。在37摄氏度时，α2C-AR保留在跨高尔基体网络中。冷却导致α2C-AR移位到细胞表面，在那里它们可以对刺激做出反应。α2C-Ars的功能挽救是由冷诱导的RhoA和Rho激酶(ROCK)激活介导的。药物阻断或RNA干扰的ROKI抑制可阻止冷诱导的α2C-ARs的动员和冷诱导的皮肤动脉收缩。我们现在证明，冷却尾动脉会导致VSM线粒体中ROS活性的快速增加，这在RhoA激活之前。事实上，抑制ROS活性可以消除冷诱导的RhoA激活和α2C-ARs的功能挽救。酪氨酸激酶抑制剂也减少了对α2C-Ars的挽救。我们认为，冷刺激线粒体产生ROS，导致受体酪氨酸激酶的反式激活和RhoA/RockI的激活，从而使α2C-ARs的空间和功能拯救成为可能。我们还在皮肤VSM中发现了一条新的环状AMP信号通路，它激活RAPL并导致Alpha2C-AR表达的显著增加。我们认为，这些调节α2C-ARs功能和表达的新途径可能参与了冷诱导的血管痉挛。事实上，我们提出了一种新的冷诱导血管痉挛模型，这种模型是由一种导致人类雷诺病的化疗药物产生的。该模型显示VSMα2C-AR活性的选择性和戏剧性增加，这导致皮肤动脉的血管痉挛。提出了三个具体的目标来追求这些新的和令人兴奋的发现，并调查它们的生理和病理生理学意义。

DESCRIPTION (provided by applicant): During cold exposure, cutaneous blood flow is reduced to prevent heat loss. This is mediated by increased sympathetic tone and a cold-induced sensitization of cutaneous arteries to constriction by norepinephrine. The latter effect is mediated by cold-induced amplification of (alpha2-adrenergic receptor (alpha2-AR) function. Although alpha2-ARs comprise 3 subtypes, only alpha2C-ARs respond to cold. Although alpha2C-ARs are not functional at 37 degrees C, they are entirely responsible for the cold-induced amplification of alpha2-AR constriction. At 37 degrees C, alpha2C-ARs are retained in the transGolgi network. Cooling causes alpha2C-AR translocation to the cell surface where they can respond to stimulation. The functional rescue of alpha2C-ARs is mediated by cold-induced activation of RhoA and rho kinase (ROCK). ROCKI inhibition by pharmacological blockade or RNA interference prevents cold-induced mobilization of alpha2C-ARs and cold-induced constriction in cutaneous arteries. We now demonstrate that cooling of tail arteries causes a rapid increase in ROS activity in VSM mitochondria, which precedes RhoA activation. Indeed, inhibition of ROS activity abolished cold-induced activation of RhoA and the functional rescue of alpha2C-ARs. The rescue of alpha2C-ARs was also reduced by a tyrosine kinase inhibitor. We propose that cold stimulates mitochondrial generation of ROS, causing transactivation of a receptor tyrosine kinase and activation of RhoA/ROCKI, enabling the spatial and functional rescue of alpha2C-ARs. We have also identified a novel cyclic AMP signaling pathway in cutaneous VSMs, which activates Rapl and causes profound increases in alpha2C-AR expression. We propose that these novel pathways for regulating the function and expression alpha2C-ARs may contribute to cold-induced vasospasm. Indeed, we present a new model of cold-induced vasospasm, generated by a chemotherapeutic agent that causes Raynaud's Disease in humans. This model displays a selective and dramatic increase in VSM alpha2C-AR activity, which precipitate vasospasm of cutaneous arteries. Three specific aims are proposed to pursue these novel and exciting findings and to investigate their physiological and pathophysiological significance.