Abstract
The interactions of 9-aminoacridine with ionic channels were studied in internally perfused squid axons. The kinetics of block of Na channels with 9-aminoacridine varies depending on the voltage-clamp pulses and the state of gating machinery of Na channels. In an axon with intact h gate, the block exhibits frequency- and voltage-dependent characteristics. However, in the pronase-perfused axon, the frequency- dependent block disappears, whereas the voltage-dependent block remains unchanged. A time-dependent decrease in Na currents indicative of direct block of Na channel by drug molecule follows a single exponential function with a time constant of 2.0 +/- 0.18 and 1.0 +/- 0.19 ms (at 10 degrees C and 80 m V) for 30 and 100 microM 9- aminoacridine, respectively. A steady-state block can be achieved during a single 8-ms depolarizing pulse when the h gate has been removed. The block in the h-gate intact axon can be achieved only with multiple conditioning pulses. The voltage-dependent block suggests that 9-aminoacridine binds to a site located halfway across the membrane with a dissociation constant of 62 microM at 0 m V. 9-Aminoacridine also blocks K channels, and the block is time- and voltage-dependent.
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Selected References
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- Armstrong C. M., Bezanilla F., Rojas E. Destruction of sodium conductance inactivation in squid axons perfused with pronase. J Gen Physiol. 1973 Oct;62(4):375–391. doi: 10.1085/jgp.62.4.375. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Armstrong C. M. Inactivation of the potassium conductance and related phenomena caused by quaternary ammonium ion injection in squid axons. J Gen Physiol. 1969 Nov;54(5):553–575. doi: 10.1085/jgp.54.5.553. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Armstrong C. M. Interaction of tetraethylammonium ion derivatives with the potassium channels of giant axons. J Gen Physiol. 1971 Oct;58(4):413–437. doi: 10.1085/jgp.58.4.413. [DOI] [PMC free article] [PubMed] [Google Scholar]
- BAKER P. F., HODGKIN A. L., SHAW T. I. Replacement of the protoplasm of a giant nerve fibre with artificial solutions. Nature. 1961 Jun 3;190:885–887. doi: 10.1038/190885a0. [DOI] [PubMed] [Google Scholar]
- Courtney K. R. Mechanism of frequency-dependent inhibition of sodium currents in frog myelinated nerve by the lidocaine derivative GEA. J Pharmacol Exp Ther. 1975 Nov;195(2):225–236. [PubMed] [Google Scholar]
- HODGKIN A. L., HUXLEY A. F. A quantitative description of membrane current and its application to conduction and excitation in nerve. J Physiol. 1952 Aug;117(4):500–544. doi: 10.1113/jphysiol.1952.sp004764. [DOI] [PMC free article] [PubMed] [Google Scholar]
- HODGKIN A. L., HUXLEY A. F. The dual effect of membrane potential on sodium conductance in the giant axon of Loligo. J Physiol. 1952 Apr;116(4):497–506. doi: 10.1113/jphysiol.1952.sp004719. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Hille B. Local anesthetics: hydrophilic and hydrophobic pathways for the drug-receptor reaction. J Gen Physiol. 1977 Apr;69(4):497–515. doi: 10.1085/jgp.69.4.497. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Mrose H. E., Ritchie J. M. Local Anesthetics: do benzocaine and lidocaine act at the same single site? J Gen Physiol. 1978 Feb;71(2):223–225. [PMC free article] [PubMed] [Google Scholar]
- TAYLOR R. E. Effect of procaine on electrical properties of squid axon membrane. Am J Physiol. 1959 May;196(5):1071–1078. doi: 10.1152/ajplegacy.1959.196.5.1071. [DOI] [PubMed] [Google Scholar]
- Woodhull A. M. Ionic blockage of sodium channels in nerve. J Gen Physiol. 1973 Jun;61(6):687–708. doi: 10.1085/jgp.61.6.687. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Wu C. H., Narahashi T. Mechanism of action of propranolol on squid axon membranes. J Pharmacol Exp Ther. 1973 Jan;184(1):155–162. [PubMed] [Google Scholar]
- Yeh J. Z., Armstrong C. M. Immobilisation of gating charge by a substance that simulates inactivation. Nature. 1978 Jun 1;273(5661):387–389. doi: 10.1038/273387a0. [DOI] [PubMed] [Google Scholar]
- Yeh J. Z., Narahashi T. Kinetic analysis of pancuronium interaction with sodium channels in squid axon membranes. J Gen Physiol. 1977 Mar;69(3):293–323. doi: 10.1085/jgp.69.3.293. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Yeh J. Z., Oxford G. S., Wu C. H., Narahashi T. Interactions of aminopyridines with potassium channels of squid axon membranes. Biophys J. 1976 Jan;16(1):77–81. doi: 10.1016/S0006-3495(76)85663-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Yeh J. Z. Sodium inactivation mechanism modulates QX-314 block of sodium channels in squid axons. Biophys J. 1978 Nov;24(2):569–574. doi: 10.1016/S0006-3495(78)85403-4. [DOI] [PMC free article] [PubMed] [Google Scholar]