Quinine blocks specific gap junction channel subtypes

被引:155
作者
Srinivas, M [1 ]
Hopperstad, MG [1 ]
Spray, DC [1 ]
机构
[1] Yeshiva Univ Albert Einstein Coll Med, Dept Neurosci, Bronx, NY 10461 USA
关键词
D O I
10.1073/pnas.191206198
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
We demonstrate that the antimalarial drug quinine specifically reduces currents through gap junctions formed by some connexins (Cx) in transfected mammalian cells, but does not affect other gap junction types, Quinine blocked Cx36 and Cx50 junctional currents in a reversible and concentration-dependent manner with half maximal blocking concentrations of 32 and 73 muM, respectively; Hill coefficients for block by quinine were about 2 for both connexins. In contrast, quinine did not substantially block gap junction channels formed by Cx26, Cx32, Cx40, and Cx43, and only moderately affected Cx45 junctions. To determine the location of the binding site of quinine (pKa = 8.7), we investigated the effect of quinine at various external and internal pH values and the effect of a permanently charged quaternary derivative of quinine. Our results indicate that the binding site for quinine is intracellular, possibly within the pore. Single-channel studies indicated that exposure to quinine induced slow transitions between open and fully closed states that decreased open probability of the channel. Quinine thus offers a potentially useful method to block certain types of gap junction channels, including those between neurons that are formed by Cx36. Moreover, quinine derivatives that are excluded from other types of membrane channels may provide molecules with connexin-specific as well as connexin-selective blocking activity.
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页码:10942 / 10947
页数:6
相关论文
共 39 条
[11]  
He DS, 2000, CIRC RES, V86, pE104
[13]   Properties of gap junction channels formed by Cx46 alone and in combination with Cx50 [J].
Hopperstad, MG ;
Srinivas, M ;
Spray, DC .
BIOPHYSICAL JOURNAL, 2000, 79 (04) :1954-1966
[14]   INTERACTION OF ANESTHETICS WITH ELECTRICAL SYNAPSES [J].
JOHNSTON, MF ;
SIMON, SA ;
RAMON, F .
NATURE, 1980, 286 (5772) :498-500
[15]   A NOVEL ACTION OF QUININE AND QUINIDINE ON THE MEMBRANE CONDUCTANCE OF NEURONS FROM THE VERTEBRATE RETINA [J].
MALCHOW, RP ;
QIAN, HH ;
RIPPS, H .
JOURNAL OF GENERAL PHYSIOLOGY, 1994, 104 (06) :1039-1055
[16]   PROPERTIES OF GAP JUNCTION CHANNELS FORMED OF CONNEXIN-45 ENDOGENOUSLY EXPRESSED IN HUMAN HEPATOMA (SKHEP1) CELLS [J].
MORENO, AP ;
LAING, JG ;
BEYER, EC ;
SPRAY, DC .
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY, 1995, 268 (02) :C356-C365
[17]  
NARAHASH.T, 1970, J PHARMACOL EXP THER, V171, P32
[18]  
O'Brien J, 1998, J NEUROSCI, V18, P7625
[19]   Localization of a voltage gate in connexin46 gap junction hemichannels [J].
Pfahnl, A ;
Dahl, G .
BIOPHYSICAL JOURNAL, 1998, 75 (05) :2323-2331
[20]   Modulation of cardiac gap junctions: The mode of action of arachidonic acid [J].
SchmilinskyFluri, G ;
Valiunas, V ;
Willi, M ;
Weingart, R .
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, 1997, 29 (06) :1703-1713