alpha2C Adrenergic Receptors & Cutaneous Circulation

描述（由申请人提供）：在冷暴露期间，皮肤血流减少，以防止热量损失。这是由交感神经张力增加和冷诱导的皮肤动脉对去甲肾上腺素收缩的敏感性介导的。后一种效应是由α 2-肾上腺素能受体（α 2-AR）功能的冷诱导扩增介导的。虽然α 2-AR包含3种亚型，但只有α 2C-AR对寒冷有反应。虽然alpha 2-C-AR在37 ℃下不起作用，但它们完全负责alpha 2-AR收缩的冷诱导扩增。在37 ℃时，alpha 2C-AR保留在transGolgi网络中。冷却导致α 2C-AR易位到细胞表面，在那里它们可以对刺激做出反应。alpha 2C-AR的功能性拯救由RhoA和rho激酶（ROCK）的冷诱导活化介导。通过药理学阻断或RNA干扰抑制ROCKI可防止冷诱导的α 2C-AR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，ROS活性的抑制消除了冷诱导的RhoA激活和α 2C-AR的功能性拯救。酪氨酸激酶抑制剂也减少了α 2C-AR的拯救。我们认为，寒冷刺激线粒体产生ROS，引起受体酪氨酸激酶的反式激活和RhoA/ROCKI的激活，使空间和功能救援的α 2C-AR。我们还在皮肤VSM中鉴定了一种新的环AMP信号通路，其激活Rapl并导致α 2C-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有助于冷诱导的血管痉挛。事实上，我们提出了一个新的模型，冷诱导血管痉挛，产生的化疗剂，导致雷诺氏病在人类。该模型显示VSM α 2C-AR活性的选择性和显著增加，其促使皮肤动脉的血管痉挛。提出了三个具体的目标，追求这些新的和令人兴奋的发现，并调查其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.