The concept of transmitter receptors: 100 years on.

It is nearly one hundred years since John Langley of Cambridge developed the idea of the 'receptive substance' or 'receptors' as we now call them. This historical review traces the background to his introduction of this concept of the transmitter receptor and of how succeeding generations built on his ideas to generalise the applicability of this concept to synapses in general. It starts with a consideration of the discovery by Bernard (1844) that curare could paralyse rabbits without affecting their hearts because, as Vulpian (1866) suggested, curare acts on some intermediate zone between nerve and muscle. No further progress could be made without establishing the idea of chemical transmission, which Elliott (1904) then achieved, building on observations concerning sympathetic transmission to smooth muscle made previously by his mentor Langley (1901). Then between 1905 and 1907 Langley, in a wonderful act of creative ability, carried out a series of experiments on the somatic neuromuscular junction which established the idea of transmitter receptors. This review gives details of the experiments which persuaded both Langley and a recalcitrant Ehrlich that pharmacological substances could possess the necessary structure for them to combine with appropriate molecules on cells. The subsequent identification by Dale and his colleagues (1936) of acetylcholine as the transmitter acting on the receptors first discovered by Langley at the somatic neuromuscular junction as well as of acetylcholine on receptors in the heart by Loewi (1921) is then detailed. The review concludes with the triumph of the first recordings of the electrical signs of single channel openings by Neher and Sakmann (1976) at the receptors which Langley had first described.