Table of Contents

December 2004; 4 (6)




  • Combination drug therapies exist that combat HIV replication and the production of virions. But just as the easiest way to deal with an interloper is to keep him from entering your home rather than removing him after the fact, most studies directed at reducing HIV infection are designed to keep HIV at bay, outside the host cell. Work on keeping HIV out has progressed from early work on CD4 to the chemokine receptors CCR5 and CXCR4 found on the surface of host cells. More recently, the depletion of cholesterol, the presence of which is essential for HIV entry, has been studied as a means to subvert HIV entry, and new work by Finnegan and others suggest that another useful strategy may involve increasing the amount of the sphingolipid ceramide found in lipid rafts on the surface of host cells. Increased ceramide might inhibit HIV entry by a number of means, including the displacement of cholesterol and modifying the overall organization and structure of the lipid rafts.

  • Research on olfaction has been fraught with considerable frustration because none of the hundreds of olfactory receptors make it to the cell surface on their own when expressed in heterologous systems. Recent work indicates that the heterodimerization of olfactory receptors with β2-adrenergic receptors results in surface expression of these G protein–coupled receptors. Similar conclusions—that heterodimerization is essential for surface expression of olfactory receptors—have been drawn from research in Drosophila utilizing completely different knockout and functional approaches. Together these findings may unlock the solution to a problem that has plagued the molecular study of olfaction since the cloning of the first olfactory G protein–coupled receptor over twelve years ago.

  • Gene expression arrays allow researchers to profile the differences between cell lines or tissues and they may identify genetic markers of development, organ maturation, or tumor progression. Although a primary tumor that grows in a host and a tumor-cell-line derived from that primary tumor and grown in vitro share similar gene expression profiles, there are, not unexpectedly, some important differences. In fact, Stein and colleagues have found that genes that are differentially expressed in primary tumors as compared to the specific genes expressed in their cell-line derivatives are more reliably predictive of tumor tractability. Thus, sensitivity in vitro might not reflect sensitivity in vivo. Because anti-tumor compounds are largely evaluated in cell culture assays, these compounds' therapeutic utility must be judged in light of genes described by Stein et al. that better predict tractability.


  • It might not be too much of a stretch to sum up the Dark Ages of receptor biology by invoking Sidney Harris's famous cartoon of two scientists standing at the blackboard where, in the middle of a written mathematical proof, one scientist has written, "Then a miracle occurs." The meticulous research of Paul Ehrlich branded the beginnings of this research field, as we know it, with no small degree of sophistication, and one wonders what he would have accomplished with modern-day technology. Moving from concepts of selectivity and preferential distribution, other researchers demonstrated the concept of concentration-dependent antagonism. More modern analyses engendered the concepts of affinity, relative potency, radioligand binding, culminating in the contemporary study of signal transduction and molecular mechanisms of disease.

  • G protein–coupled receptors constitute the most common protein class to be targeted by modern drugs-and by modern drug developers. Nevertheless, the crystal structure of only one GPCR (i.e., Rhodopsin) has been solved, and with at least 700 GPCRs in the human genome, the design of specific GPCR-targeting drugs poses a formidable challenge. Computer modeling and ligand docking are enabling researchers to determine the consequences of structurally altering both GPCRs and their ligands, offering important insights into GPCR function and routes to drug design. Purine receptors are exemplary GPCRs in a number of contexts, and ongoing investigations suggest that ligand design may be—literally—only half of the battle in the future of certain GPCR-based therapies.

  • Small monomeric G proteins of the Rho family interact with a variety of effector and regulatory proteins to regulate signaling cascades that involve protein phosphorylation and dephosphorylation. The contraction of vascular smooth muscle is becoming increasingly recognized as a context in which Rho has clinical implications. Rat models of hypertension, along with an increasing variety of pharmacological tools, have established that at least one Rho protein (i.e., RhoA) can contribute to vascular disease. Indeed, the finding that the widely prescribed statins inhibit the isoprenyl modification and Rho may suggest that therapeutic modulation of Rho is already in practice. Cellular responses that emanate from Rho signaling in vascular disease likely engage the regulation of nitric oxide synthase activity and culminate in smooth muscle cell migration, contraction, and DNA synthesis.

Beyond the Bench

Net Results