Those receptors at the neuromuscular junction and in the electric organ of Torpedo have been studied much more than those in the CNS, but they all have similar characteristics. The peripheral receptor has four different protein subunits a, p, y and ^ but is pentameric with the a always doubled. In the CNS the receptors are less complex. Most have just two subunits a and p, but are again pentameric with 2a and 3p subunits situated around and forming the ion channel. Several variations of the a subunit, from a2-a9 (a1 in periphery) and three in the p give the possibility for a number of different heteromeric receptors, although a4 and p2 predominate and receptors with the configuration a42 and p23 (2 of a4 and 3 of p3) show the highest affinity for ACh. Homomeric assembled receptors of just a7 subunits are also found. Each subunit folds into a four-transmembrane domain (mi m2 m3 m4) with the m3-m4 loop linkage in the cytoplasm and the terminal amine and carboxyl groups extracellular (Fig. 6.4). (The accepted scheme for subunit and configuration numbering is outlined in Chapter 3).

The amino-acid sequence of each subunit is known and they are characteristic of a NT receptor that directly gates ion channels. Activation of the receptor requires 2 ACh molecules to combine with two a subunits. Pharmacologically it is not easy to distinguish between central and peripheral nicotinic receptors, let alone their variants. Those in the CNS are more like those found in peripheral ganglia than at the neuromuscular junction and are more readily blocked by dihydro-P-erythroidine than curare. Receptors containing a4p2 subunits (the majority) are also not blocked by a-bungarotoxin but bind a shorter kappa or 'neuronal' bungarotoxin. Those receptors with the a7 subunit, for which a-bungarotoxin has high affinity, will, however, bind that toxin.

Although drugs may not be able to distinguish between the subclasses of nicotinic receptor the last few years has seen the breeding of knock-out mice in which most of the

The Function The Brain Drugs


Guanylate influx cyclase cyclase en lux


Guanylate influx cyclase cyclase en lux









Figure 6.4 Schematic representation of the muscarinic receptor. All muscarinic receptors have seven transmembrane domains and the major difference between them is within the long cytoplasmic linkage connecting the fifth and sixth domains. This implies different G-protein connections and functions. Some possibilities are shown although the position of the M1 and M2 boxes is not intended to indicate their precise structural differences within the loop mamalian nAChR subunits have been selectively deleted (see Cordero-Erausquin et al. 2000). While only those mice lacking subunits found mainly in peripheral nicotinic receptors (e.g. a3 and ¬Ņ64) do not survive, others show little change in spontaneous behaviour but some reduced responses (less antinociception) to nicotine.

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