Seven-transmembrane receptors, which constitute the largest, most ubiquitous and most versatile family of membrane receptors, are also the most common target of therapeutic drugs. Recent findings indicate that the classical models of G-protein coupling and activation of second-messenger-generating enzymes do not fully explain their remarkably diverse biological actions.

Seven-transmembrane receptors.

The adenylate cyclase system, which consists of a catalytic moiety and regulatory guanine nucleotide-binding proteins, provides the effector mechanism for the intracellular actions of many hormones and drugs. The tissue specificity of the system is determined by the particular receptors that a cell expresses. Of the many receptors known to modulate adenylate cyclase activity, the best characterized and one of the most pharmacologically important is the beta-adrenergic receptor (beta AR). The pharmacologically distinguishable subtypes of the beta-adrenergic receptor, beta 1 and beta 2 receptors, stimulate adenylate cyclase on binding specific catecholamines. Recently, the avian erythrocyte beta 1, the amphibian erythrocyte beta 2 and the mammalian lung beta 2 receptors have been purified to homogeneity and demonstrated to retain binding activity in detergent-solubilized form. Moreover, the beta-adrenergic receptor has been reconstituted with the other components of the adenylate cyclase system in vitro, thus making this hormone receptor particularly attractive for studies of the mechanism of receptor action. This situation is in contrast to that for the receptors for growth factors and insulin, where the primary biochemical effectors of receptor action are unknown. Here, we report the cloning of the gene and cDNA for the mammalian beta 2AR. Analysis of the amino-acid sequence predicted for the beta AR indicates significant amino-acid homology with bovine rhodopsin and suggests that, like rhodopsin, beta AR possesses multiple membrane-spanning regions.

Cloning of the gene and cDNA for mammalian β -adrenergic receptor and homology with rhodopsin

Receptor-effector coupling by G proteins

A family of proteins called G proteins couples cell surface receptors to a variety of enzymes and ion channels. Since many cells contain several very similar G proteins, an important question is how signals remain specific as they cross the cell membrane.

Roles of G protein subunits in transmembrane signalling.

The phosphoinositides are minor phospholipids present in all eukaryotic cells. They are storage forms for messenger molecules that transmit signals across the cell membrane and evoke responses to extracellular agonists. The phosphoinositides break down to liberate messenger molecules or precursors of messenger molecules. Many different compounds are formed, although the functions of only a few are understood. Recent studies elaborating the pathways for formation of products from phosphoinositides and the factors controlling their metabolism are summarized here.

https://science.sciencemag.org/content/sci/234/4783/1519.full.pdf

The metabolism of phosphoinositide-derived messenger molecules

Reconstitution of a hormone-sensitive adenylate cyclase system. The pure beta-adrenergic receptor and guanine nucleotide regulatory protein confer hormone responsiveness on the resolved catalytic unit.

J Winslow

Papers

Reconstitution of a hormone-sensitive adenylate cyclase system. The pure beta-adrenergic receptor and guanine nucleotide regulatory protein confer hormone responsiveness on the resolved catalytic unit.