The role of acid sensing ion channels in the cardiovascular function

Abstract

Acid Sensing Ion Channels (ASIC) are proton sensors involved in several physiological and pathophysiological functions including synaptic plasticity, sensory systems and nociception. ASIC channels have been ubiquitously localized in neurons and play a role in their excitability. Information about ASIC channels in cardiomyocyte function is limited. Evidence indicates that ASIC subunits are expressed in both, plasma membrane and intracellular compartments of mammalian cardiomyocytes, suggesting unrevealing functions in the cardiomyocyte physiology. ASIC channels are expressed in neurons of the peripheral nervous system including the nodose and dorsal root ganglia (DRG), both innervating the heart, where they play a dual role as mechanosensors and chemosensors. In baroreceptor neurons from nodose ganglia, mechanosensation is directly associated with ASIC2a channels for detection of changes in arterial pressure. ASIC channels expressed in DRG neurons have several roles in the cardiovascular function. First, ASIC2a/3 channel has been proposed as the molecular sensor of cardiac ischemic pain for its pH range activation, kinetics and the sustained current. Second, ASIC1a seems to have a critical role in ischemia-induced injury. And third, ASIC1a, 2 and 3 are part of the metabolic component of the exercise pressure reflex (EPR). This review consists of a summary of several reports about the role of ASIC channels in the cardiovascular system and its innervation.

Recent progress in understanding the intracellular domain's gating and functional roles in trimeric ligand-gated ion channels

“…ASIC参与多种病理生理过程，包括缺血性卒中、精神疾病、神经退行性疾病、心血管疾病、疼痛、恐惧条件反射以及学习记忆等 ［ 59 - 60 ］ ，ASIC胞内区域在疾病的发生发展中起到一定的作用（ 图3 B）。ASIC3是不同类型疼痛模型的重要参与者，最新研究发现ASIC1b参与了外周疼痛的疾病过程：c-Jun氨基末端激酶可增强ASIC1b和ASIC3的活性，主要依赖于ASIC1b氨基末端的Ser59和ASIC3羧基末端的Thr512磷酸化，提示胞内区域的磷酸化可能在包括ASIC1b和/或ASIC3参与的炎症、神经病理性疼痛和偏头痛等多种病理生理疼痛过程中具有重要作用 ［ 61 ］ 。ASIC1a胞内区域控制着细胞死亡途径的启动，而细胞死亡与脑卒中等缺血性疾病相关 ［ 62 - 63 ］ 。脑卒中时细胞外溶液的pH值下降可导致ASIC1a构象变化，暴露出羧基端的RIPK1结合位点，而生理pH条件下ASIC1a的氨基端和羧基端会形成一个复合物，堵塞RIPK1的结合位点，这项研究为脑卒中药物的设计提供了新见解：稳定氨基端和羧基端之间的复合物或破坏羧基端与RIPK1相互作用 ［ 63 ］ 。相关研究也证实了RIPK1与ASIC1a的相互作用可能介导了炎症、缺血性脑卒中、神经创伤和癫痫发作的脊髓小脑性共济失调等多种疾病 ［ 64 - 65 ］ 。 表2 对本文中所涉及的ASIC不同亚型胞内区域作用位点及相应功能进行了总结。…”