Table of Contents

February 2005; 5 (1)

Speaking of Pharmacology


  • Many drugs are removed from the body through a multistep process that includes covalent conjugation, transport into the bile, and excretion. Bile acids are transported across the ileocyte apical (brush border) membrane by the apical sodium-dependent bile-acid transporter (Asbt), but the identity of the primary transporter responsible for moving bile acids across the basolateral membrane of the ileocyte has remained a mystery, although not for a lack of protein pretenders to the throne. Recent insights from transcriptional profiling studies of wild-type and Asbt-deficient mice indicate that a complex formed by the organic solute carrier proteins α and β (Ostα and Ostβ) is the primary transporter for basolateral bile acid transport.

  • The renin-angiotensin system (RAS) acts to regulate blood volume and arterial pressure, and has direct effects on the heart. Renin, released by the kidney, circulates and acts—in the rate-limiting step of angiotensin II (Ang II) production—to convert angiotensinogen to inactive angiotensin I (Ang I). Ang II constricts vessels, leading to increased arterial pressure, among other effects. Components of the RAS have been found in a number of extra-renal tissues. Recent research indicates that mast cells in the heart may produce renin, creating a cardiac-specific RAS that acts locally to produce Ang II. These results, however, are not without controversy. Others have searched for sites of renin production and have found no other significant source that was physiologically important or that could not be completely ruled out as a possible contaminant. How important is mast cell–synthesized renin for direct cardiac-related effects?

  • Radiation therapy is utilized as a treatment to cure or manage cancer; however, because of risk to local healthy tissue—and a modest success rate of some radiotherapy—strategies have been sought that would increase the therapeutic index of the treatment while reducing damage to surrounding tissue. Cell and tissue irradiation stimulates a series of biochemical and molecular signals; various components of this ionizing radiation (IR)-inducible signal transduction cascade can promote the survival of tumor cells. Identification of interactions between IR and a signaling pathway creates an opportunity to target those signaling intermediates to improve the outcome of radiotherapy. The epidermal growth factor receptor (EGFR, also termed ErbB1) is involved in normal development and differentiation of epithelial cells as well as in tumorigenesis. The EGFR is activated by IR, thus making this receptor and other members of the ErbB family important targets for radiosensitizing molecular interventions. Recent approaches have utilized monoclonal antibodies, small molecules, and transgenic technologies to undermine the kinase activity of EGFR.


  • Over the past two decades, new techniques in brain imaging have detailed neuroanatomical and neurophysiological changes associated with drug abuse and addiction. But clinically, addiction to drugs of abuse is defined in terms ofbehavior, and the propensity to become addicted to one drug as opposed to another—or to be rehabilitated, by alternative treatments, from addictive behaviors—can only be assessed as a matter of options available from a repertoire of possible behaviors. A quantitative measure of the ways that organisms negotiate such options is provided by the field of behavioral economics. By appraising drug use in terms of commodity demand, behavioral economists are able to measure the relative propensities for diverse drugs to become addictive and to model alternative treatments of addiction.

  • With approximately 1000 G protein–coupled receptors (GPCRs) in the human proteome, the selective regulation of G protein–transduced signals is an inordinately complicated task. The aptly named regulators of G protein signaling (RGS) are a family of proteins that interact primarily with Gα subunits and help integrate diverse signaling pathways. The role of RGS proteins in coordinating basic aspects of cell signaling appears to be pivotal in a number of respects, including both acute and chronic cellular responses to drugs of abuse. The expression of a number of RGS proteins is modulated in response to opioids and stimulants, and this modulation occurs in brain regions that are key to the elaboration of adaptive responses to drugs, including sensitization, dependence, and tolerance. A better understanding of RGS proteins in these processes may lead to novel targets for the treatment of drug addiction.

  • Neuropeptide S (NPS) occurs in a great variety of animal species, including humans, and manifests intriguing properties that make it unique among neurotransmitters, and indeed, among known pharmacological agents. Like hypocretin (orexin), NPS signals through a GPCR that until recently had remained “orphanized.” And like hypocretin, NPS appears to play a role in the regulation of sleep/wakefulness. When administered centrally, however, NPS not only promotes wakefulness, but exerts anxiolytic effects. NPS may thus hold the key to the development of novel drugs to combat symptoms of somnolence without causing anxiogenesis.

Beyond the Bench

Net Results