Abstract
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 outer medullary potassium channel(+), and H(2)O channels and some exchangers (i.e. Na(+)/H(+)) and co-transporters (Na(+)-HCO(3)(minus sign), Na(+)-K(+)-2Cl(-)). Acid-sensitive ion channels (ASICs), members of the epithelial sodium channel/degenerin superfamily, were originally cloned 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 Delta 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 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.
Highlights
Hyperactivated Naϩ absorption through epithelial sodium channel (ENaC)1 is important in the pathophysiology of cystic fibrosis (CF [1,2,3,4,5])
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
CFTR Co-localizes with ASIC2a—ASIC2a and CFTR were detected in rat anterior hypothalamus by indirect immunofluorescence (Fig. 1)
Summary
Hyperactivated Naϩ absorption through epithelial sodium channel (ENaC) is important in the pathophysiology of cystic fibrosis (CF [1,2,3,4,5]). Interaction of CFTR and ASICs ologically identified in rat brain (36 – 40), human hypothalamus [41], and a murine neuronal cell line established from the hypothalamus [42]. In these same groups of neurons where CFTR is found, ASIC1a and ASIC2a are expressed [17]. To investigate the possible functional regulation by neuronal CFTR on ASIC1a/2a, the objective of the present study was to use Xenopus oocytes as an expression model to study the effect of human CFTR on the channel activity of ASIC1a/2a. Our results show that CFTR up-regulates proton-gated Naϩ currents by altering the kinetics of extracellular Naϩ interaction with ASIC1a/2a
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