ÿþFirst, ASICs are expressed in muscle afferents at higher levels than converse white leather in cutaneous afferents, and they are activated in the narrow ranges of extracellular pH and other metabolites that occur during muscle ischemia and exercise ( Molliver et al., 2005 ; Light et al., 2008 ). We found that ASIC-like currents are generated in <"70% of labeled muscle afferents, and the subunit composition is a unique heteromeric channels consisting primarily of ASIC1a and "3 subunits, with a lesser contribution from ASIC2 subunits ( Gautam and Benson, 2013 ). Second, ASICs are required for the development of normal muscle pain.

Cystic fibrosis transmembrane conductance regulator (CFTR) functions as both a chloride channel and an epithelial transport regulator, interacting with Na (epithelial sodium channel), Cl " , renal comme des garcons converse outer medullary potassium channel , and H 2 O channels and some exchangers ( i.e. Na /H ) and co-transporters (Na -HCO , Na -K -2Cl " ). Acid-sensitive ion channels (ASICs), members of the epithelial sodium channel/degenerin superfamily, were originally cloned converse all stars from neuronal tissue, and recently localized in epithelia. Because CFTR has been immunocytochemically and functionally identified in rat, murine, and human brain, the regulation of ASICs by CFTR was tested in oocytes.

Our observations show that the proton-gated Na current formed by the heteromultimeric ASIC1a/2a channel was up-regulated by wild type but not by ”F508-CFTR. In contrast, the acid-gated Na current associated with either the homomultimeric ASIC1a or ASIC2a channel was not influenced by wild type CFTR. The apparent equilibrium dissociation constant for off white converse extracellular Na for ASIC1a/2a was increased by CFTR, but CFTR had no effect on the gating behavior or acid sensitivity of ASIC1a/2a. CFTR had no effect on the pH activation of ASIC1a/2a. We conclude that wild type CFTR elevates the acid-gated Na current of ASIC1a/2a in part by altering the kinetics of extracellular Na interaction.

A new subfamily of the ENaC/DEG superfamily, the acid-sensing ionic channels (ASICs), has recently been identified ( 17 ). Like other family members, ASICs are thought to have a single, large extracellular loop, and two short transmembrane domains with both the C and N termini located intracellularly ( 17 ). ASICs are ligand-gated ion channels activated by extracellular acidification and perhaps mechanical stimulation. The biophysical and pharmacological characteristics of ASICs are similar to those of ENaC, albeit with a lower sensitivity to amiloride ( K i <" 10 ¼ m versus 0.1 ¼ m ) and a converse cdg different cation permeability pattern ( 17 ).

The current-voltage (I-V) relationships were acquired by stepping the holding potential in 20-mV increments from "100 to 100 mV. The effects of bath solution acidification (pH 4.0) on the resting membrane potential were recorded, and acid-gated Na entry through ASICs was measured. Data for voltage and current clamps were sampled at the rate of 1 kHz and filtered at 500 kHz. Experimental protocols were controlled by pCLAMP 8.2 software (Axon Instruments, Burlingame, CA), and Na currents at "60 mV were digitized and stored on the hard drive of a computer for later analysis.