The inhibitory effect of trimethylamine on the anticonvulsant activities of quinine in the pentylenetetrazole model in rats.
ABSTRACT Quinine specifically blocks connexin 36 (Cx36), one of the proteins that form gap junction channels. Quinine suppressed ictal epileptiform activity in in vitro and in vivo studies without decreasing neuronal excitability. In this study, we considered the possible mechanism of anticonvulsant effects of quinine (1, 250, 500, 1000 and 2000 microM, i.c.v.) in the pentylenetetrazole (PTZ) model of seizure. Thus, we used trimethylamine (TMA) (0.05 microM, 5 microM, 50 microM), a gap junction channel opener, to examine whether it could reverse the effects of quinine in rats. Intracerebroventricular (i.c.v.) injection of quinine affected generalized tonic-clonic seizure (GTCS) induced by PTZ by increments in seizure onset and reducing seizure duration. Additionally, pretreatment with different doses of TMA (i.c.v.) attenuated the anticonvulsant effects of quinine on the latency and duration of GTCS. It can be concluded that quinine possesses anticonvulsant effects via modulation of gap junction channels, which could contribute to the control of GTCS.
- SourceAvailable from: pnas.org[show abstract] [hide abstract]
ABSTRACT: 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 microM, 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.Proceedings of the National Academy of Sciences 10/2001; 98(19):10942-7. · 9.74 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: The pH of the cytoplasm (pHt) measured with pH-sensitive microelectrodes in cleavage-stage blastomeres of amphibian (Ambystoma) and teleost (Fundulus) embryos is about 7.7. In electrotonically coupled cell pairs, junctional conductance is rapidly and reversibly reduced by acidification of the cytoplasm. The relation between junctional conductance and pHi is the same for increasing and decreasing pH and is independent of the rate of change over a wide range. The relation is well fitted by a Hill curve with K = 50 nM (pK = 7.3) and n = 4 to 5. The closure of gap junction channels at low pHi appears to be a cooperative process involving several charged sites. The absence of hysteresis and identity of effects for fast and slow pHi changes implies that protons act directly on the channel macromolecules and not through an intermediate in the cytoplasm.Science 03/1981; 211(4483):712-5. · 31.03 Impact Factor
- [show abstract] [hide abstract]
ABSTRACT: Whole-cell/voltage-clamp recordings were made from dissociated bullfrog sympathetic neurons to examine the sensitivity of potassium currents to a potassium channel blocker quinine (1-500 microM). Among three currents tested, a rapidly inactivating A-type current (I(A)) was the most sensitive to the block by quinine (IC50 approximately 22 microM). A non-inactivating M-type current (I(M)) was the least sensitive (IC50 approximately 445 microM), and the sensitivity of a slowly inactivating delayed rectifier-type current (I(K)) was in between (IC50 approximately 115 microM). Results suggest that the ability of quinine to block different types of potassium currents such as I(A) and I(M) with significantly different IC50 values would be of help for the potassium channel pharmacology in amphibian autonomic ganglion cells.Neuroscience Letters 12/1999; 275(2):121-4. · 2.03 Impact Factor