AbstractThis paper summarizes observations and spec‐ulations concerning the origin and chemical na‐ture of the synaptic receptors, i.e., the transmitter‐and drug‐sensitive sites present in the postsynaptic membranes. Available evidence suggests that receptors are synthesized in the cytoplasm of the postsynaptic cell. However their appearance in a functional (“receptive”) condition in the sur‐face of this cell is under the direct control of the presynaptic nerve endings.It is likely that such regulatory influence is exerted by a receptor‐controlling, inhibitory com‐pound which is released by the nerve endings, perhaps together with the transmitter. However, unlike the transmitter, the inhibitory compound would be taken up by the postsynaptic cell. The manner in which this inhibitory factor acts is unknown. It may block the synthesis of receptor molecules. Alternatively, it may exert a masking action on receptors already present in the surface of the cell, which would remain in a dormant or silent condition.The changes which follow chronic denervation of skeletal muscle (a marked increase in the transmitter‐sensitive areas of the membrane) can be explained by assuming that the neural inhibi‐tory compound slowly disappears from the muscle cell after being disconnected from its motor nerve. As a consequence, silent receptors become active or new receptors are synthesized. The receptor‐controlling compound would also leak from the muscle fiber at points where the muscle membrane has been damaged.Since almost the only active receptors present in normal muscle are located at the subsynaptic area of the membrane, where the receptor‐controlling factor should be expected to reach highest concentrations, the existence of a second factor which blocks or prevents receptor inhibition is postulated. This factor may be the transmitter itself.Speculations on the chemical nature of recep‐tors have favored the idea that they may be protein molecules bound to, or embodied into, the membrane structure. Attempts to isolated chem‐ically the receptor substance have so far been inconclusive mainly because a receptor molecule, or molecular complex, separated from the cell ceases to behave as a receptor though it may still combine with the transmitter.The idea that receptors may be protein mole‐cules has received considerable support from recent work on the mechanism of the Schultz‐Dale reaction in denervated, immunologically sensitized diaphragmatic muscle from the guinea‐pig. With the aid of a microtap which allows the rapid application of protein to discrete areas of the surface of muscle fibers, it has been shown that antigens do exert a depolarizing action on sensi‐tized muscle cells by decreasing the electrical resistance of their surface membrane.It can be concluded from these experiments that antibody molecules bound to the surface of denervated muscle fibers behave as receptors for the specific antigens. The physical changes which take place in the muscle membrane, following their interaction with antigens, are similar to those elicited by acetylcholine on the cholinergic recep‐tors of the same cells.Artificial models of transmitter‐receptor sys‐tems have been built by using artificial lipid films treated with antibodies and enzymes. The transverse impedance of such films, presumably coated with protein molecules, decreases when the specific antigens or substrates are introduced in the system.The results support the idea that synaptic receptors are protein molecules which, synthesized by the postsynaptic cytoplasm, locate themselves in the membrane, the permeability of which they regulate, possibly by virtue of configura‐tional changes. Such changes are in turn con‐trolled by the combination of the active site of the receptor, i.e., the receptor surface, with specific molecules of transmitters and drugs.