Alpha and beta adrenergic and muscarinic cholinergic receptor structure

Purification and characterization of the neurotransmitter receptors of the autonomic nervous system have revealed considerable structural and functional homology between these pharmacologically distinct classes of information transduction molecules. Alpha 1- and alpha 2-adrenergic receptors are single polypeptides with molecular mass 85,000 Da and pI 4.6. Beta 1- and beta 2-adrenergic receptors are single polypeptides with molecular mass 68,000 Da and pI 5.0. Muscarinic cholinergic receptors from a variety of tissues and species are single polypeptides with molecular mass 80,000 Da and pI 4.2. Proteolytic digestion and analysis of affinity-labelled adrenergic and cholinergic receptors indicates a striking similarity in the number and sizes of peptides produced. Topographical analysis of the receptors has shown that they have a similar membrane orientation with more than half of the protein exposed to the extracellular environment. Peptide-mapping studies of soluble and membrane-bound receptors suggest that the ligand-binding domain of adrenergic and cholinergic receptors is localized near the end of the protein that is exposed to the extracellular environment. The marked similarity between alpha- and beta-adrenergic and muscarinic cholinergic receptor structure is perhaps not unexpected in light of the fact that these receptors interact with the same transmitters (in the case of alpha- and beta-adrenergic receptors) and/or with the same effector proteins in the membrane (stimulatory and inhibitory guanine nucleotide regulatory proteins, ion channels). Yet, depending on the tissue distribution of receptors and their effectors, this limited number of proteins can modulate dramatically different physiological effects. It may be that the differences in pharmacological specificity of ligand binding and the differences in receptor-effector interactions observed among adrenergic receptor subtypes and muscarinic cholinergic receptors are due to minor structural differences within the active sites of these proteins. Obviously, the real answers as to the extent of structural homology between the receptor classes will be derived from the amino acid sequencing of the purified proteins or from the cloning of the receptor genes and recently the genes coding for the beta-adrenergic receptor have been cloned and sequenced from human brain, hamster lung, and turkey erythrocytes. Comparison of the derived protein sequences reveals a high degree of structural homology between the avian and mammalian receptors with approximately 50% primary sequence identity and highly conserved secondary structure.(ABSTRACT TRUNCATED AT 400 WORDS)