Table of Contents

August 2004; 4 (4)




  • μ-Opioid receptor agonists are commonly utilized as analgesics for treatment of acute pain and some chronic pain syndromes. In addition to their outstanding effectiveness, opioids, unfortunately, promote respiratory depression. Indeed, opioid–induced respiratory depression can result in hypoventilation and neurologic injury, and may arise as a consequence of μ-opioid receptor–mediated blockade of specialized respiratory neurons in the brainstem. Manzke and coworkers have suggested that the serotonin receptor subtype 5-HT4a (5-HT4aR) could serve as a useful therapeutic target for the treatment or prevention of opioid–induced respiratory depression. This hypothesis derives from the finding that the 5-HT4aR and the μ-opioid receptors affect the intracellular concentration of cyclic AMP in opposing ways. The findings are a significant milestone in ongoing efforts to understand the analgesia–ventilation link.


  • Heterotrimeric Gαβγ 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 Gα forms has been recognized for some time, but it is also becoming clear that the β- and γ-subunits exist in varying forms that, in heterodimeric combinations, can specify alternative downstream signals as well as interact selectively with particular Gα 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 Gα, Gβ, and Gγ species, including their associations with other proteins.

  • 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.

  • 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.

Beyond the Bench

Net Results