Molecular physiology of CFTR Cl- channels in heart.
Recent electrophysiological data suggests a number of similarities in the properties of cAMP-dependent Cl- channels in heart and cAMP-dependent Cl- channels encoded by the cystic fibrosis transmembrane conductance regulator (CFTR) gene product in various epithelial cells. We tested the hypothesis that cAMP-dependent Cl- channels in heart may be due to cardiac expression of CFTR by amplification and sequencing of several regions of CFTR from myocardial tissue derived from various species and areas of the heart. Regions corresponding to the first nucleotide binding domain (NBD1), transmembrane segments I-VI (TS I-VI), transmembrane segments VII-XII (TS VII-XII), and the regulatory domain (R domain) were amplified and sequenced from rabbit ventricle (see Fig. 1). Comparison of the known amino acid sequence of human epithelial CFTR with the deduced sequence from rabbit heart indicated deletion of exon 5 in the first cytoplasmic loop of TS I-VI suggesting that CFTR is an alternatively spliced isoform in rabbit ventricle. Outside of the alternatively spliced region, the heart CFTR Cl- channel isoform displayed greater than 95% identity to human epithelial CFTR Cl- channels. We have also compared the molecular distribution of the CFTR gene product to the distribution of cAMP-dependent Cl- channels in native cardiac myocytes derived from various species and areas of the heart. Amplification of regions corresponding to NBD1, R domain, and TS VII-XII from atrium and ventricle of guinea pigs, rabbit, and dog hearts exhibited a distribution which closely matched the distribution of cAMP-dependent Cl- channels assessed using electrophysiological techniques.(ABSTRACT TRUNCATED AT 250 WORDS)
Hume
J R
JR
Department of Physiology, University of Nevada School of Medicine, Reno 89557-0046, USA.
Hart
P
P
Levesque
P C
PC
Collier
M L
ML
Geary
Y
Y
Warth
J
J
Chapman
T
T
Horowitz
B
B
D000595:Amino Acid Sequence; D000818:Animals; D018118:Chloride Channels / Q000502:physiology*; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000494:pharmacology; D003550:Cystic Fibrosis / Q000235:genetics*; D004285:Dogs; D006168:Guinea Pigs; D006321:Heart / Q000502:physiology*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics; D008969:Molecular Sequence Data; D011817:Rabbits
D018118:Chloride Channels; D008565:Membrane Proteins; D005576:Colforsin; D000242:Cyclic AMP