Modulation of drug block of the cardiac potassium channel KCNA5 by the drug transporters OCTN1 and MDR1.
OBJECTIVE
A common site for drug binding on voltage-gated ion channels is at the interior face of the channel pore. In this study, we tested the hypothesis that the extent of drug block of the human cardiac KCNA5 (K(v) 1.5) channel underlying the atrial-specific, ultra-rapidly activating, delayed K(+) current (I(Kur) ) is modulated by the drug uptake and efflux transporters encoded by organic cation transporter 1 (OCTN1) and multiple drug-resistant gene 1 (MDR1) and expressed in human heart.


METHODS
Drug block of KCNA5 was assessed in Chinese hamster ovary cells transiently transfected with KCNA5 alone or in combination with the OCTN1 or MDR1 transporter construct, as well as in an MDR1 stably expressed cell line.


RESULTS
Co-expression of OCTN1 significantly facilitated block by quinidine (10 µM), verapamil (20 µM), propafenone (5 µM) and clofilium (30 µM). Further evidence of drug transport modulating drug block was the finding that with OCTN1, block developed faster and only partially washed-out, and that block potentiation was prevented by cimetidine, an inhibitor of OCTN1. MDR1 expression attenuated KCNA5 block by erythromycin (an MDR1 substrate). Block was restored by reversin-205 (10 µM, an MDR1 inhibitor). MDR1 did not affect KCNA5 inhibition by KN-93 (1 µM), a blocker acting on the outer mouth of the channel pore.


CONCLUSIONS
The extent of drug block of KCNA5 can be modulated by drug uptake and efflux transporters. These data provide further support for the idea that modifying intracellular drug concentrations could modulate the effects of blocking ion channels in patients.
Yang
Tao
T
Oates Institute for Experimental Therapeutics, Departments of Pharmacology and Medicine, University Medical Center, Vanderbilt University School of Medicine, 2215-B Garland Avenue, Nashville, TN 37232-0575, USA. tao.yang@vanderbilt.edu
McBride
Brian F
BF
Leake
Brenda F
BF
Kim
Richard B
RB
Roden
Dan M
DM
D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001665:Binding Sites; D001692:Biological Transport; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D005786:Gene Expression Regulation; D006801:Humans; D051666:Kv1.5 Potassium Channel / Q000037:antagonists & inhibitors*; D027701:Organic Cation Transport Proteins / Q000378:metabolism*; D011485:Protein Binding; D013552:Swine; D027981:Symporters
C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000889:Anti-Arrhythmia Agents; D051666:Kv1.5 Potassium Channel; D027701:Organic Cation Transport Proteins; C109807:SLC22A4 protein, human; D027981:Symporters