Historical review: A brief history and personal retrospective of seven-transmembrane receptors

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Abstract

Pharmacologists have studied receptors for more than a century but a molecular understanding of their properties has emerged only during the past 30–35 years. In this article, I provide a personal retrospective of how developments and discoveries primarily during the 1970s and 1980s led to current concepts about the largest group of receptors, the superfamily of seven-transmembrane (7TM) receptors [also known as G-protein-coupled receptors (GPCRs)]. Significant technical advances such as the development of methods for radioligand binding, solubilization and purification of the β2-adrenoceptor and other adrenoceptors led to the cloning of receptor genes and the discovery of their 7TM architecture and homology with rhodopsin. A universal mechanism of receptor regulation by G-protein-coupled receptor kinases (GRKs) and arrestins, originally discovered as a means of ‘desensitizing’ G-protein-mediated second-messenger generation, was subsequently found to mediate both receptor endocytosis and activation of a growing list of signaling pathways such as those involving mitogen-activated protein kinases. Numerous opportunities for novel therapeutics should emerge from current and future research on 7TM receptor biology.

Section snippets

Early antecedents

Although the earliest discussion of ‘binding’ of biologically active molecules to specific sites on cells is generally attributed to Ehrlich, it was Langley and his student Dale, working together during the first decade of the 20th century, who first explicitly stated the idea of a ‘receptive substance’ on reactive cells [4]. Their deductions were based on classical physiological and pharmacological experiments using isolated skeletal or smooth muscle preparations, or submandibular salivary

Biochemical effectors of receptor action

The 1960s and 1970s witnessed the beginning of a merger between biochemistry and pharmacology. This was led by biochemists such as Sutherland, Krebs and Rodbell, who turned their attention to studying the molecular basis of hormone and drug action. This led, in relatively quick succession, to a series of seminal discoveries that were to shape all further work in the field. Sutherland discovered the second messenger cAMP, which mediates the actions of dozens of receptors, and the enzyme adenylyl

Molecular era of receptor research

The era of molecular research on the receptors (studies that assess receptor properties directly, rather than inferring them from downstream effector function) can reasonably be dated to ∼1970. A remarkable fact about this period, difficult to imagine now, is that despite decades of physiological and biochemical work, the physical existence of receptors remained controversial. A sense of this skepticism is apparent in a statement made by Ahlquist. A prominent pharmacologist of the time,

Radioligand binding

If a single technical advance can be said to have opened the door to the molecular era of receptor research, it was the development of radioligand binding methods during the 1970s. These methods, which were developed at about the same time for several receptors now known to be 7TM receptors (recently reviewed for the opioid peptide receptors [21]) and for the nicotinic acetylcholine receptor, transformed the field of receptor research. These methods led rapidly to new insights into the dynamic

Receptor purification and reconstitution

Perhaps the most important consequence of the ability to tag receptors directly was that it opened the way to receptor purification. In contrast to the situation with the nicotinic acetylcholine receptor and rhodopsin, no highly enriched sources of most GPCRs exist. However, working together with Joseph Pitha and Marc Caron, we developed a highly effective and specific affinity chromatography resin for the purification of the β2-adrenoceptor 25, 26, 27. During the next several years,

Receptor cloning

Although only relatively small amounts of β2-adrenoceptor were obtained by purification, with advances in microsequencing techniques by the mid-1980s, this was sufficient to obtain small stretches of peptide sequence from peptides derived from the receptors. This enabled the design of oligonucleotide probes that could be used to clone the genes and/or cDNAs encoding the receptors. This led, in 1986, to an important breakthrough: the cloning of the gene and cDNA encoding the hamster β2

Mutagenesis and chimeric receptors

With the availability of clones for a rapidly increasing number of receptors, the scientific community turned its attention to unraveling the structural features that determine receptor function. Extensive mutagenesis studies carried out in many laboratories quickly established the major principles 54, 55. The internal loops of the receptors, particularly those regions in closest proximity to the plasma membrane in addition to the proximal portions of the C-terminal tail, engaged the G

Constitutively active mutant receptors

Another serendipitous consequence that followed the chimeric receptor work was the discovery of constitutively active mutant receptors. Thus, unexpectedly, when another fellow in my laboratory, Susanna Cotecchia, replaced just four residues in the third cytoplasmic loop of the α1B-adrenoceptor with residues from the β2-adrenoceptor, the α1B-adrenoceptor acquired the ability to signal constitutively: that is, in the absence of agonist [59]. It was ultimately found that virtually any substitution

Arrestins and G-protein-coupled receptor kinases (GRKs): a universal mechanism of 7TM receptor regulation

As described earlier, the cloning of the β2-adrenoceptor in 1986 and the appreciation that it and rhodopsin were structurally related, founding members of a large receptor gene family represented an important milestone. However, almost simultaneously two other distinct streams of research were converging that would also reveal the close relationship between these two receptors, and by obvious extension, a relationship that would ultimately extend to the large 7TM receptor family. This research

β-Arrestins and GRKs in endocytosis and signaling

Completely unsuspected at the time of their discovery was the fact that the biological functions of β-arrestins and GRKs extend well beyond ‘desensitization’ of the receptors. Thus, in recent years, β-arrestins have been shown to serve as agonist-dependent adaptors that link the receptors both to elements of the clathrin-dependent endocytic machinery and to a growing list of signaling proteins 83, 84, 85. Interaction of β-arrestins with clathrin, adaptor protein 2 (AP2), the small G protein

Future perspectives and opportunities

The discoveries of the past 30 years have transformed receptors from abstract physiological concepts into physicochemical entities. They have revealed pervasive, even universal, principles concerning their structure, function and regulation. Today, there are many hot topics in the field of 7TM receptor biology, several of which are likely to lead to new and/or improved therapeutics. A few that I consider to be of most importance are listed below.

  • (i)

    Attempts to crystallize the receptors and

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