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

Molecular Basis of Cardiac Cl- Channels. Recent electrophysiologic stu dies have provided evidence suggesting that as many as six different C l- conductances can be identified in the sarcolemma of cardiac myocyte s isolated from various animal species and areas of the heart, These i nclude Cl- conductances activated by stimulation of protein kinase A, protein kinase C, extracellular ATP, intracellular Ca2+, membrane stre tch, 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 c AMP-activated Cl- conductance is due to cardiac expression of an isofo rm of the cystic fibrosis transmembrane conductance regulator (CFTR) C l- 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 determi ne if the molecular distribution of CFTR matches the distribution of c AMP-dependent Cl- channels in native myocytes, Amplification of region s corresponding to the first nucleotide binding domain (NBD1), transme mbrane segments (TS) VII-XII, and the regulatory (R) domain showed a p recise correlation to tissues that electrophysiologically exhibit sarc olemmal cAMP-dependent Cl- channels, whereas region TS I-VI exhibited a distribution independent of the presence of cAMP-dependent Cl- chann els, 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 explanati on for the anomalous expression of this region of CFTR in cardiac tiss ues that do not exhibit cAMP-dependent Cl- currents but do exhibit oth er types of macroscopic Cl- currents may be sequence homology in a mol ecularly conserved pore region common to different types of cardiac Cl - channels.