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Paradoxically, the combined power of patch clamping and of molecular genetic methods has caused a return to an age of stamp collecting. At almost daily intervals new ion channels are cloned and characterized, but in many cases evidence for their physiological importance is flimsy or nonexistent. The best known of all receptors--the nicotinic acetylcholine receptor--provides a good example.
The nicotinic receptor in muscle and ganglia was the first ligand-gated receptor to be identified (by Langley, who 90 years ago coined the term "receptor" in reference to it); it was the receptor that inspired the first derivation of the Langmuir equation by A. V. Hill (1); it was the first receptor shown to mediate transmission at chemical synapses (by Dale and his colleagues in the 1930s); and it was the first to be purified and cloned (in the 1980s) (2). The nicotinic acetylcholine receptor provided the first detailed description of fast synaptic transmission (largely by Katz and his colleagues) (2), the first recordings of single-ion channels, and the first detailed kinetic analysis (3). At the molecular level, this receptor has the best-described three-dimensional structure (4).
From 1951 (5) onward, it became clear that the nicotinic receptor in autonomic ganglia was not quite the same as that on skeletal muscle fibers, but apart from that, all was simple. Fast nicotinic synapses were supposed to be absent from the brain (except at Renshaw cell synapses, which are formed in the spinal cord by collaterals of motor axons), the main fast transmitter in the central nervous system (CNS) being glutamate. The brain does have neurons that contain and release acetylcholine, but this acetylcholine was thought to act on the relatively slow, GTP-binding protein (G protein)--coupled muscarinic receptors. Then, in 1986, results obtained with in situ hybridization suggested that, quite unexpectedly, nicotinic receptors were abundant in many parts of the brain (6). What are they doing there? As yet, nobody really knows, because fast nicotinic synapses still cannot be found in the brain. But a new report by McGehee and co-workers in this issue of Science (7) sheds new light on the question by showing that nicotine enhances excitatory transmission in the CNS by acting on presynaptic nerve endings to increase transmitter release.
Nicotinic receptors from muscle are oligomers of...