Autonomic Nervous System

Nicotinic receptors were initially characterized on the basis of their responses to selective agonists and antagonists (see Figures 4.4-4.7; McGehee and Role, 1995). In nAChR research, the use of neuronal toxins as antagonists has highlighted the existence of multiple nAChR subtypes, as well as emphasizing the difficulties in the pharmacological approach to delineating these subtypes. A number of snake-derived toxins occupy one or both of the agonist binding sites on nAChRs and prevent agonist-induced opening of channels (Arias, 2000). A major dilemma for nAChR pharmacology throughout the 1970s involved the snake toxin, a-bungarotoxin (a-BnTx), shown to be a potent antagonist of nAChRs in skeletal muscle. Numerous studies demonstrated that radiolabeled a-BnTx could bind with high affinity to neuronal preparations of both sympathetic and parasympathetic autonomic ganglia; however, a functional block of cholinergic synaptic transmission in autonomic ganglia using the toxin was not convincingly shown, except in cases where toxin purity was questionable. This work has been reviewed in detail by Chiapinelli (1985), and will not be revisited here. The obvious conclusion from these studies was that radioligand binding studies had revealed the presence of a-BnTx binding sites, while functional pharmacological studies, mainly using physiological assays, revealed that this a-BnTx-binding site was not responsible for mediating synaptic transmission in autonomic ganglia.

Subsequently, a second snake toxin, previously called toxin F and now K-BnTx, was found to block synaptic transmission or responses to applied nAChR agonists in autonomic ganglia (Ravdin and Berg, 1979; Chiapinelli, 1983; Chiapinelli and Dryer, 1984; Loring et al., 1984; Loring and Zigmond, 1988). Localization studies using the two toxins suggest that, as expected, K-BnTx labels synaptic sites in the ganglia (Loring and Zigmond, 1987), while a-BnTx labels extrasynaptic sites (Jacob and Berg, 1983; Fumagalli and De Renzis, 1984; Loring et al., 1985). It is now known that a-BnTx labels homomeric a7 and a9 nAChRs, whereas K-BnTx labels a2p2, a3p2, a4p2 and a3p4 type nAChRs (McGhee and Role, 1995). It should be

FIGURE 4.3 Expression of individual mRNAs encoding subunits of nAChRs in superior cervical ganglion neurons (SCG). Panels show dark field micrographs following emulsion autoradiography with (a) a3, (b) P4, (c) a4-1 antisense probes: (d) shows control with P4 sense probe (from Rust et al., 1994, with permission).

FIGURE 4.3 Expression of individual mRNAs encoding subunits of nAChRs in superior cervical ganglion neurons (SCG). Panels show dark field micrographs following emulsion autoradiography with (a) a3, (b) P4, (c) a4-1 antisense probes: (d) shows control with P4 sense probe (from Rust et al., 1994, with permission).

noted that, despite its name, the neurotoxin K-BnTx does not block all neuronal nAChRs and, at high concentrations, can block muscle AChRs (Sargent, 1993) (Figure 4.3).

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