Receptor proteins for all hydrophilic extracellular small-molecule, peptide, and protein signaling molecules are located on the surface of the target cell. The signaling molecule, or ligand, binds to a site on the extracellular domain of the receptor with high specificity and affinity. Ligand binding depends on multiple weak, noncovalent forces (i.e., ionic, van der Waals, and hydrophobic interactions) and molecular complementarity between the interacting surfaces of a receptor and ligand (see Figure 2-12). Like an enzyme, each type of receptor binds only a single type of signaling molecule or a group of very closely related ones. For example, the growth hormone receptor binds to growth hormone, but not to other hormones with very similar, though not identical, structures. Similarly, acetylcholine receptors bind only this small molecule and not others that differ from it only slightly in chemical structure, while the insulin receptor binds insulin and related hormones called insulin-like growth factors 1 and 2 (IGF-1 and IGF-2), but no other hormones. The binding specificity of a receptor refers to its ability to bind or not bind closely related substances.

Binding of ligand to receptor causes a conformational change in the receptor that initiates a sequence of reactions leading to a specific response inside the cell. Organisms have evolved to be able to use a single ligand to stimulate different cells to respond in distinct ways. Different cell types often have different receptors for the same ligand, and activation of each receptor type induces a different intracellular signal transduction pathway. For instance, the surfaces of skeletal muscle cells, heart muscle cells, and the pancreatic acinar cells that produce hydrolytic digestive enzymes each have different types of receptors for acetylcholine. In a skeletal muscle cell, release of acetylcholine from a motor neuron innervating the cell triggers muscle contraction by activating an acetylcholine-gated ion channel. In heart muscle, the release of acetylcholine by certain neurons activates a G protein–coupled receptor and slows the rate of contraction and thus the heart rate. Acetylcholine stimulation of pancreatic acinar cells triggers a rise in the concentration of cytosolic Ca²⁺ that induces secretion of the digestive enzymes stored in secretory granules to facilitate digestion of a meal. Thus the activation by acetylcholine of different types of acetylcholine receptors that are expressed in different cell types leads to different cellular responses.

Alternatively, the same receptor may be found on various cell types in an organism, but binding of a particular ligand to the receptor triggers a different response in each type of cell, given the particular complement of proteins expressed by the cell. The same epinephrine receptor (the β-adrenergic receptor) is found on liver, muscle, and fat (adipose) cells; as we will see in Section 15.5, it stimulates depolymerization of glycogen to glucose in the first two cell types, but hydrolysis and secretion of stored fat in adipose cells. In these ways, the same ligand can induce different cells to respond in a variety of ways, often in a manner that coordinates the overall response of the organism. This property is known as the effector specificity of the receptor-ligand complex.