Table of Contents

December 2005; 5 (6)


Speaking of Pharmacology

Nascent Transcripts


  • Bacteria posses multiple two component regulatory systems consisting typically of a kinase and a transcription factor that, in concert, monitor the concentrations of particular extracellular factors and regulate specific gene expression accordingly. Salmonella possess PhoP-PhoQ, which are activated under conditions of suboptimal [Mg2+] and result in gene expression leading to greater stability of the outer membrane. New research identifies PhoQ as a receptor for sublethal concentrations of antimicrobial peptides (AMPs), adapting bacteria for survival. The development of AMPs that do not activate Phop-PhoQ, however, should proceed with great caution: AMPs are part of the host innate immune response and bacterial resistance to newly developed AMPs could possibly lead to intractable infection in immunocompetent hosts.

  • Conventional dogma holds that steroid hormones traverse cell membranes passively, owing to their lipophilic nature. The recently characterized protein megalin, however, functions as a transport protein on cell surfaces to carry steroids across the plasma membrane. Upon hydrolysis of steroid-associated binding globulins in lysosomes, free hormone is liberated and may exert its effects in the cell. Megalin-independent mechanisms of steroid uptake are likely important too, as the phenotypes of megalin-deficient mice do not completely mimic the phenotypes of androgen receptor– or estrogen receptor–null mice.

  • The peptide Angiotensin II (Ang II), part of the renin-angiotensin system (RAS), participates in the control of systemic arterial pressure. Ang II participates in increasing smooth muscle tone, and its positive effects on smooth muscle cell DNA synthesis are inhibited by treatment with prazosin, an α1-adrenoceptor agonist. Ang II also induces the expression of α1-adrenoceptor, especially the α1D subtype. Other findings suggest that the molecular signals activated by Ang II and by α1D-adrenoceptor might interweave, thus leading to the augmentation of smooth muscle tone and hypertension.


  • From bone density and reproductive behavior to cardiovascular and immune system effects, estrogens regulate the function of several organs and systems. Although attributed with potent and multifunctional effects, estrogen and its receptors do not work alone. Several coregulatory proteins have been found that modulate the activities of the estrogen receptors ERα and ERβ. By understanding how these coactivators and co-repressors work, we may be able to target these proteins for molecular intervention in sex hormone–related diseases.

  • It has been over a decade since ceramide kinase (CERK) and its product, ceramide-1-phosphate (C1P), were first reported. Since its cloning, in 2002, CERK has been the subject of an explosion of publications concerning various signal transduction pathways. The roles of this previously overlooked enzyme, as well as those of its product C1P, continue to expand, and their regulatory functions in the production of eicosanoid inflammatory mediators are proving essential to fundamental signal transduction pathways. In particular, C1P is required for the activation and translocation of cPLA2α, the initial rate-limiting step of eicosanoid synthesis. The potential for inhibitors of CERK to offer a new generation of anti-inflammatory and anti-cancer therapeutics is especially deserving of further study.

  • Chemotherapy typically involves administering very strong drugs that affect the more sensitive tumor mass but may also affect the rest of the patient's body. Antibody-based therapies have the potential to target tumors very specifically. Several different approaches to antibody conjugation are under investigation, including the addition of enzymes (that activate systemically administered prodrugs at the tumor) or radionuclides (that emit alpha particles or beta rays that kill tumor cells and minimal adjacent healthy tissue). Additionally, antibodies can be created whose two complementarity determining regions (CDRs, the highly specific antigen binding sites) recognize different antigens, further enhancing the complexity and utility of these therapeutics.

Beyond the Bench

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