Smooth muscle acid‐sensing ion channel 1: pathophysiological implication in hypoxic pulmonary hypertension

Abstract

What is the topic of this review? An increase in pulmonary arterial smooth muscle cell intracellular Ca(2+) levels facilitates the enhanced vasoconstrictor and vascular remodeling responses associated with hypoxic pulmonary hypertension. Identifying the mechanisms of altered Ca(2+) homeostasis will advance our understanding of the pathogenesis of pulmonary hypertension and identify potential therapeutic targets. What advances does it highlight? Acid sensing ion channel 1 (ASIC1), present in pulmonary arterial smooth muscle cells, contributes to enhanced Ca(2+) entry and is an important constituent to the active vasoconstriction, vascular remodeling, and right ventricular hypertrophy associated with hypoxic pulmonary hypertension. Acid-sensing ion channels (ASICs) belong to the amiloride-sensitive, degenerin/epithelial sodium channel superfamily. Acid-sensing ion channels are voltage-independent, proton-gated cation channels, and their activity has been linked to a variety of physiological and pathological functions in the central and peripheral nervous system. Nonetheless, ASICs are expressed in a variety of tissues. In this review, we describe a novel role for ASIC1 in regulating pulmonary arterial smooth muscle cell (PASMC) Ca(2+) influx in both physiological and pathophysiological settings. Through a store-operated mechanism, ASIC1 contributes to pulmonary vasoconstriction elicited by various agonists and alveolar hypoxia. The ASIC1-mediated Ca(2+) entry in PASMCs is a central component of the active vasoconstriction, vascular remodelling and right ventricular hypertrophy associated with the development of hypoxic pulmonary hypertension. Despite the requirement for ASIC1 to enhance Ca(2+) influx in the pulmonary hypertensive circulation, these responses are not dependent on an increase in PASMC ASIC1 protein expression, suggesting that hypoxia promotes activation of ASIC1 through other regulatory mechanism(s). Here, I describe some of the correlations between hypoxia-induced changes in homeostasis of reactive oxygen species with that of ASIC1 function. Ultimately, a better understanding of the molecular mechanisms by which ASICs are regulated will help to elucidate their mechanism of action and identify potential therapeutics that specifically target ASICs.

Ion Channels in Pulmonary Hypertension: A Therapeutic Interest?

“…ASICs are voltage-independent amiloride-sensitive and proton-gated cation channels, and their activity has been linked to a variety of physiological and pathological functions in the central and peripheral nervous system. The ASIC family of channel is constituted by five genes (ACN1–ACN5) encoding at least seven subunits (ASIC1a, -1b, -2a, -2b, -3, -4 and -5) [ 218 ]. The subunit composition of ASIC mainly determines the pH sensitivity and gating characteristics of the channel.…”

“…The subunit composition of ASIC mainly determines the pH sensitivity and gating characteristics of the channel. However, Acid sensing ion channel 1 (ASIC1) is expressed in a variety of tissues including PASMC, whose contribute to enhanced Ca 2+ entry mediating vasoconstriction, vascular remodeling, and right ventricular hypertrophy associated with hypoxic PH [ 218 , 219 ]. ASIC channels are mainly permeable to Na + but also conduct Ca 2+ [ 219 ].…”

Revisiting the Role of TRP, Orai, and ASIC Channels in the Pulmonary Arterial Response to Hypoxia

“…This model is consistent with the ability of different sub-types of Stim, TRPC, and Orai proteins to generate SOCE in pulmonary arteries ( Fernandez et al, 2012 ; Earley and Brayden, 2015 ; Wang et al, 2017 ). Moreover, other TRP channels such as transient receptor potential vanilloid-4 (TRPV4) and structurally unrelated Na + - and Ca 2+ -permeable cation channels such as acid-sensing ion channels-1 (ASIC1) may also contribute to SOC signaling in PASMC ( Goldenberg et al, 2015 ; Jernigan, 2015 ). Whether the mechanism linking store depletion and ASIC1 activation to generate SOCE is related with association of ASIC1 with Stim, Orai, TRPC proteins, or other unknown signal has not been elucidated.…”

Acid-sensing ion channels contribute to the effect of extracellular acidosis on proliferation and migration of A549 cells

“…[19][20][21] In addition, ASICs are also present in non-neuronal tissues such as testis, bone, dendritic cells, vascular smooth muscles, and endothelial cells. [22][23][24] Many reports have shown that ASICs play an important role in acidosis-associated physiological and pathological functions. 23,[25][26][27][28][29] Recent studies have shown that ASICs are expressed in glioma cells and mammary carcinoma and are involved in tumor pathogenesis.…”