Biomaterial Database

Local anesthetic block of batrachotoxin-resistant muscle Na+ channels. 1998

G K Wang, and C Quan, and S Y Wang

Department of Anesthesia, Harvard Medical School and Brigham & Women's Hospital, Boston, Massachusetts 02115, USA.

Local anesthetics (LAs) are noncompetitive antagonists of batrachotoxin (BTX) in voltage-gated Na+ channels. The putative LA receptor has been delineated within the transmembrane segment S6 in domain IV of voltage-gated Na+ channels, whereas the putative BTX receptor is within segment S6 in domain I. In this study, we created BTX-resistant muscle Na+ channels at segment I-S6 (micro1-N434K, micro1-L437K) to test whether these residues modulate LA binding. These mutant channels were expressed in transiently transfected human embryonic kidney 293T cells, and their sensitivity to lidocaine, QX-314, etidocaine, and benzocaine was assayed under whole-cell, voltage-clamp conditions. Our results show that LA binding in BTX-resistant micro1 Na+ channels was reduced significantly. At -100 mV holding potential, the reduction in LA affinity was maximal for QX-314 (by 17-fold) and much less for neutral benzocaine (by 2-fold). Furthermore, this reduction was residue specific; substitution of positively charged lysine with negatively charged aspartic acid (micro1-N434D) restored or even enhanced the LA affinity. We conclude that micro1-N434K and micro1-L437K residues located near the middle of the I-S6 segment of Na+ channels can reduce the LA binding affinity without BTX. Thus, this reduction of the LA affinity by point mutations at the BTX binding site is not caused by gating changes induced by BTX alone. We surmise that the BTX receptor and the LA receptor within segments I-S6 and IV-S6, respectively, may align near or within the Na+ permeation pathway.

UI	MeSH Term	Description	Entries
D008012	Lidocaine	A local anesthetic and cardiac depressant used as an antiarrhythmia agent. Its actions are more intense and its effects more prolonged than those of PROCAINE but its duration of action is shorter than that of BUPIVACAINE or PRILOCAINE.	Lignocaine,2-(Diethylamino)-N-(2,6-Dimethylphenyl)Acetamide,2-2EtN-2MePhAcN,Dalcaine,Lidocaine Carbonate,Lidocaine Carbonate (2:1),Lidocaine Hydrocarbonate,Lidocaine Hydrochloride,Lidocaine Monoacetate,Lidocaine Monohydrochloride,Lidocaine Monohydrochloride, Monohydrate,Lidocaine Sulfate (1:1),Octocaine,Xylesthesin,Xylocaine,Xylocitin,Xyloneural
D009132	Muscles	Contractile tissue that produces movement in animals.	Muscle Tissue,Muscle,Muscle Tissues,Tissue, Muscle,Tissues, Muscle
D002478	Cells, Cultured	Cells propagated in vitro in special media conducive to their growth. Cultured cells are used to study developmental, morphologic, metabolic, physiologic, and genetic processes, among others.	Cultured Cells,Cell, Cultured,Cultured Cell
D004351	Drug Resistance	Diminished or failed response of an organism, disease or tissue to the intended effectiveness of a chemical or drug. It should be differentiated from DRUG TOLERANCE which is the progressive diminution of the susceptibility of a human or animal to the effects of a drug, as a result of continued administration.	Resistance, Drug
D005041	Etidocaine	A local anesthetic with rapid onset and long action, similar to BUPIVACAINE.	2-(Ethylpropylamino)-2',6'-butyroxylidide,Duranest,W-19053,W 19053,W19053
D006801	Humans	Members of the species Homo sapiens.	Homo sapiens,Man (Taxonomy),Human,Man, Modern,Modern Man
D000779	Anesthetics, Local	Drugs that block nerve conduction when applied locally to nerve tissue in appropriate concentrations. They act on any part of the nervous system and on every type of nerve fiber. In contact with a nerve trunk, these anesthetics can cause both sensory and motor paralysis in the innervated area. Their action is completely reversible. (From Gilman AG, et. al., Goodman and Gilman's The Pharmacological Basis of Therapeutics, 8th ed) Nearly all local anesthetics act by reducing the tendency of voltage-dependent sodium channels to activate.	Anesthetics, Conduction-Blocking,Conduction-Blocking Anesthetics,Local Anesthetic,Anesthetics, Topical,Anesthetic, Local,Anesthetics, Conduction Blocking,Conduction Blocking Anesthetics,Local Anesthetics,Topical Anesthetics
D001496	Batrachotoxins	Batrachotoxin is the 20-alpha-bromobenzoate of batrachotoxin A; they are toxins from the venom of a small Colombian frog, Phyllobates aurotaenia, cause release of acetylcholine, destruction of synaptic vesicles and depolarization of nerve and muscle fibers.	Batrachotoxin B
D001566	Benzocaine	A surface anesthetic that acts by preventing transmission of impulses along NERVE FIBERS and at NERVE ENDINGS.	Ethyl Aminobenzoate,4-Aminobenzoic Acid Ethyl Ester,Americaine,Anaesthesin,Anesthesin,Bensokain,Benzocaine Acetate,Benzocaine Formate,Benzocaine Hydrobromide,Benzocaine Hydrochloride,Benzocaine Methanesulfonate,Ethoform,Acetate, Benzocaine,Formate, Benzocaine,Hydrobromide, Benzocaine,Hydrochloride, Benzocaine,Methanesulfonate, Benzocaine
D015222	Sodium Channels	Ion channels that specifically allow the passage of SODIUM ions. A variety of specific sodium channel subtypes are involved in serving specialized functions such as neuronal signaling, CARDIAC MUSCLE contraction, and KIDNEY function.	Ion Channels, Sodium,Ion Channel, Sodium,Sodium Channel,Sodium Ion Channels,Channel, Sodium,Channel, Sodium Ion,Channels, Sodium,Channels, Sodium Ion,Sodium Ion Channel