R E V I E W S:

Miller B. Jones, David P. Siderovski, and Shelley B. Hooks: The Gß ${gamma}$ DIMER as a NOVEL SOURCE of SELECTIVITY in G-Protein Signaling: GGL-ing AT CONVENTION
Mol. Interv. 2004 4: 200-214. [Summary] [Full Text] [PDF]
Heterotrimeric G ${alpha}$ ß ${gamma}$ proteins regulate the transduction of extracellular signals from a vast number of cell surface receptors. One mechanism for integrating the diverse molecular messages that are received by G protein–coupled receptors is the production of multiple isoforms of the three subunits that constitute the G protein. A multiplicity of G ${alpha}$ forms has been recognized for some time, but it is also becoming clear that the ß- and ${gamma}$ -subunits exist in varying forms that, in heterodimeric combinations, can specify alternative downstream signals as well as interact selectively with particular G ${alpha}$ isoforms. Key to developing therapeutics that can refine or limit physiological and pathophysiological G protein–propagated signals will be an understanding of the roles and combinatorial potential of distinct G ${alpha}$ , Gß, and G ${gamma}$ species, including their associations with other proteins.

Yuan-Xiang Tao and Roger A. Johns: NEURONAL PDZ DOMAINS: A Promising New Molecular Target for Inhaled Anesthetics?
Mol. Interv. 2004 4: 215-221. [Summary] [Full Text] [PDF]
Designing better inhalational anesthetics may be as simple as identifying those volatile compounds that target specific protein domains, resulting in the disruption of multiprotein complexes at synaptic termini. New research reveals that biologically useful concentrations of inhaled anesthetics can interrupt the interactions between PDZ domains and their cognate binding sites (i.e., other PDZ domains and different motifs) on other proteins. Thus, the authors point out, a sophisticated two-pronged approach to improved anesthesia might involve tailoring some compounds that target synaptic receptor activity and other compounds that target intracellular PDZ domain–mediated interactions located proximal to the synapse.

Terry Kenakin: Allosteric Modulators: The New Generation of Receptor Antagonist
Mol. Interv. 2004 4: 222-229. [Summary] [Full Text] [PDF]
The development of new drugs is frequently configured as a search for "blockers" of specific molecular signals (i.e., a search for simple competitive antagonists). In contrast, allosteric antagonists can be sought for their ability to "permit" receptor function, albeit described by altered kinetics, with regard to a particular agonist. Indeed, the use of permissive antagonists—or better said, permissive "modulators," for they may actually promote agonism—offers therapeutic modalities distinct from simple "blockers." An allosteric change that may obliterate receptor function with respect to one agonist, for example, may be inconsequential with respect to another. An appreciation of this selective aspect of allostery can thus be relevant to any attempt to "block" receptor function.

D E P A R T M E N T S:

Reflections:

Science in the cultural context

Stanley Scheindlin: Demystifying the New Drug Application
Mol. Interv. 2004 4: 188-191. [Full Text] [PDF]

CrossTalk:

Interviews with people in the world of pharmacology

: GEOFFREY BURNSTOCK: MOST HIGHLY CITED SCIENTIST
Mol. Interv. 2004 4: 192-195. [Summary] [Full Text] [PDF]

Beyond the Bench:

Representations of pharmacology and science in the media

Christie Carrico: A Book of Practical Cats
Mol. Interv. 2004 4: 230. [Full Text] [PDF]

Net Results:

Sites of interest on the World Wide Web

: Sites of interest on the World Wide Web—edited by Rick Neubig and David Roman
Mol. Interv. 2004 4: 231. [Full Text] [PDF]

Outliers:

Cartoon

ASPET Journals	Pharmacological Reviews	Drug Metabolism and Disposition
Molecular Interventions	Molecular Pharmacology	J Pharmacology and Exp Therapeutics