Acid-sensing cation channels Structure, function, and pathophysiologic implications

In both the CNS and peripheral nervous system (PNS), energy metabolism, neuronal activity, hypoxia, hypercapnia, and inflammation elicit pH fluctuations that may affect neuronal excitability and function. The acid-sensing ion channels (ASICs) are voltage-independent cation channels that are activated by acidic pH and are expressed in neurons throughout the body. ASICs belong to the degenerin/epithelial sodium (Na+) channel (DEG/ENaC) superfamily, which includes several amiloride-sensitive cation channels. ASICs are primarily permeable to Na+ and elicit cell depolarization, leading to secondary intracellular accumulation of calcium (Ca2+). ASICs in peripheral sensory neurons participate in nociception, mechanosensation, and taste transduction. In the CNS, ASICs are involved in synaptic plasticity, learning, fear conditioning, and maintenance of retinal integrity. Studies using ASIC channel blockers or transgenic mice indicate that ASICs may be involved in several neurologic disorders, including pain, cerebral ischemia, seizures, and neurodegeneration. ASICs may also have a role in anxiety and depression. Therefore, ASICs may represent novel targets for potential treatment of these disorders. The structure, function, modulation, and clinical implications of ASICs have been the subjects of several reviews.(1-10