alpha2C Adrenergic Receptors & Cutaneous Circulation

说明（由申请人提供）：在寒冷暴露期间，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冷诱导皮肤动脉对去甲肾上腺素收缩的敏感介导的。后一种效应是通过冷诱导α 2-肾上腺素能受体（α 2- ar）功能的扩增介导的。虽然alpha2-ARs包括3个亚型，但只有alpha2C-ARs对寒冷有反应。虽然alpha2c - ar在37℃下没有功能，但它们完全负责冷诱导的alpha2-AR收缩放大。在37℃时，alpha2c - ar保留在跨高尔基网络中。冷却会导致alpha2C-AR转移到细胞表面，在那里它们可以对刺激做出反应。α - 2c - ars的功能恢复是通过冷诱导RhoA和rho激酶（ROCK）的激活介导的。通过药物阻断或RNA干扰抑制ROCKI可防止冷诱导的alpha2C-ARs的动员和冷诱导的皮肤动脉收缩。我们现在证明，尾动脉的冷却导致VSM线粒体中ROS活性的快速增加，这先于RhoA激活。事实上，抑制ROS活性可以消除冷诱导的RhoA激活和α - 2c - ars的功能修复。一种酪氨酸激酶抑制剂也降低了alpha2C-ARs的拯救。我们提出，寒冷刺激线粒体生成ROS，导致酪氨酸激酶受体的反激活和RhoA/ROCKI的激活，从而使alpha2C-ARs在空间和功能上得到拯救。我们还在皮肤vsm中发现了一种新的环状AMP信号通路，该通路激活Rapl并导致alpha2C-AR表达的显著增加。我们认为这些调节α - 2c - ars功能和表达的新途径可能与冷诱导的血管痉挛有关。事实上，我们提出了一种新的冷诱导血管痉挛模型，由一种导致人类雷诺氏病的化疗药物产生。该模型显示VSM alpha2C-AR活性选择性和显著增加，从而导致皮肤动脉血管痉挛。我们提出了三个具体的目标来追求这些新颖而令人兴奋的发现，并研究它们的生理和病理生理意义。

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.