Junctional and extrajunctional acetylcholine receptors.

Abstract

Acetylcholine receptors (AchR) are being extensively studied by neurobislogists, biochemists, immunologists, pharmacologists, and cell and developmental biologists (Robertson 1979). Apart from their well-known function as a receptor for acetylcholine (Ach), their possible regulatory role in the growth of the presynaptic terminal (Freeman 1977) and their involvement in the pathological state characterized as myasthenia gravis (Kao and Drachman 1977; Weinemann et nl. 1978) are under investigation. AchR are most abundant at the electroplaques of electric fish, which provide a convenient and rich source for biochemical and structural studies (see Anonymous 1976; Weidmann and Changeux 1978). In recent years AchR from neuromuscular junctions of vertebrates have also provided a good deal of data (see Edwards 1979; Fambrough 1979). Besides, the AchR in embryonic muscles (Steinbach et al. 1979) and the extrajunctional AchR that are produced following denervatlon of adult skeletal muscle (Miledi and Potter 197 1 ; Tipnis and Malhotra 1976) are also of current interest (in particular, their role(s) and comparison with the junctional AchR). The present article, then, primarily deals with the junctional AchR and their comparison with the extrajunctional AchR in vertebrates. Dale (1 9 14) classified the AchR into nicotinic and Goodman and Gilman 1970). Nicotinic receptors are blocked by curare whereas muscarinic receptors are blocked by atropine (see Goodman and Gilman 1970). The AchR are widely distributed among invertebrates (Kehoe 1972: Kehoe et al. 1976; Dudai 1979; Ross and Triggle 1972) and vertebrates (Fambrough 1979; Vogel and Nirenberg 1976; KrnjeviC 1974). However, the electrogenic cells and their homologous skeletal muscle cells have been more thoroughly investigated with respect to the structure, characterization and biosynthesis of AchR. The AchR from both these cells are of the nicotinic type (see Karlin et al. 1976). The studies devoted towards physical and biochemical characterization have been facilitated by the availability of the specific probe 0-bungarotoxin (a-BGT) and related neurotoxins. These toxins are obtained by fractionation of crude snake venom from various species of land and sea snakes (see Lee 1979). The toxins can be conjugated to 12, horseradishperoxidase (Jacob and Lentz 1979), or ferritin (Hourani et al. 1974; Tipnis and Malhotra 1979a, 19796, 1980) for correlative biochemical and structural studies. Immunochemical techniques are also being applied for structural studies (Klymkowsky and Stroud 1979) as well as for cross-reactivity between subunits of AchR (Lindstrom 1976; Claudio and Raftery 1977). muscarinic types, depending on their sensitivity toAcetylcholine receptor complex wards nicotine and muscarine. The activation of these two receptors by a common ligand, ~ ~ h , is AchR is a glycoprotein as the receptor binds condue to the binding of the receptors to two different canavalin A (Con A) and other 'ectins (Meunier'f?t portions of the Ach molecule. The carbonyl side of al. 1974; Brockes and Hall 1957a ; Almon andAppe1 the Ach molecule reacts with the nicotinic receptor 1976b ; Boulter and Patrick 1977; Patrick et al. 1977; whereas the methyl side reacts with the muscarinic Fambrough 1979). The AchR is a transmembrane receptor (Chothia 1970). The introduction of varprotein and is exposed on both surfaces of the ious other pharmacological agents, agonists and plasma membrane (Weidmann and Changeux 2978; antagonists, has further confirmed the above two Fambrough 1979). The evidence for the transmemmain categories of AchR. For example, agonists brane nature of this protein has come from a variety like tetramethylammonium (TMA), dimethylof experimental studies. (1) X-ray diffraction studphenyl piperazinium (DMPP), phenyltrimethylamies on Torpedo californica electroplaques reveal monium (PTMA), and suxamethonium stimulate that the receptor extends by 5.5 nm on the outside nicotinic receptors whereas agents like acetyl Pand by 1.5 nm on the inside (Ross et al. 1977). The methylcholine, oxotremorine, pilocarpine, and extension of AchR beyond the bilayer has been furarecoline stimulate the muscarinic receptor (see ther demonstrated by labelling the membranes of Torp~do with rabbit and goat antireceptor antibod-