RT Journal Article
SR Electronic
T1 Structural Domains Underlying the Activation of Acid-sensing Ion Channel 2a
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.114.096909
DO 10.1124/mol.114.096909
A1 Laura-Nadine Schuhmacher
A1 Shyam Srivats
A1 Ewan St. John Smith
YR 2015
UL http://molpharm.aspetjournals.org/content/early/2015/01/12/mol.114.096909.abstract
AB The acid-sensing ion channels (ASICs) are a family of ion channels expressed throughout the mammalian nervous system. The principal activator of ASICs is extracellular protons and ASICs have been demonstrated to play a significant role in many physiological and pathophysiological processes including synaptic transmission, nociception and fear. However, not all ASICs are proton-sensitive: ASIC2a is activated by acid, whereas its splice variant ASIC2b is not. We made a series of chimeric ASIC2 proteins and using whole-cell electrophysiology we have identified the minimal region of the ASIC2a extracellular domain that is required for ASIC2 proton-activation: the first 87 amino acids after transmembrane domain 1. We next examined the function of different domains within the ASIC2b N-terminus and identified a region proximal to the first transmembrane domain that confers tachyphylaxis upon ASIC2a. We have thus identified domains of ASIC2 that are crucial to channel function and may be important for the function of other members of the ASIC family.