A PLETHORA OF CARDIAC CHLORIDE CONDUCTANCES - MOLECULAR DIVERSITY OR A RELATED GENE FAMILY

Molecular Basis of Cardiac Cl- Channels. Recent electrophysiologic studies have provided evidence suggesting that as many as six different Cl- conductances can be identified in the sarcolemma of cardiac myocytes isolated from various animal species and areas of the heart, These include Cl- conductances activated by stimulation of protein kinase A, protein kinase C, extracellular ATP, intracellular Ca2+, membrane stretch, and a basally active Cl- conductance. Many basic biophysical and pharmacologic properties of these channels are presently unknown, and the only molecular information presently available suggests that the cAMP-activated Cl- conductance is due to cardiac expression of an isoform of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl- channel normally found in epithelial cells, We used the polymerase chain reaction (PCR) to amplify four distinct regions corresponding to the cardiac CFTR gene product from several cardiac tissues to determine if the molecular distribution of CFTR matches the distribution of cAMP-dependent Cl- channels in native myocytes, Amplification of regions corresponding to the first nucleotide binding domain (NBD1), transmembrane segments (TS) VII-XII, and the regulatory (R) domain showed a precise correlation to tissues that electrophysiologically exhibit sarcolemmal cAMP-dependent Cl- channels, whereas region TS I-VI exhibited a distribution independent of the presence of cAMP-dependent Cl- channels, Since the TS I-VI region of the CFTR gene product is believed to comprise the pore region of the channel, we propose that one explanation for the anomalous expression of this region of CFTR in cardiac tissues that do not exhibit cAMP-dependent Cl- currents but do exhibit other types of macroscopic Cl- currents may be sequence homology in a molecularly conserved pore region common to different types of cardiac Cl- channels.