Table of Contents

October 2005; 5 (5)

Speaking of Pharmacology


Nascent Transcripts


  • During a genomic survey of the transparent sea squirt (Ciona intestinalis), Murata et al. discovered a gene that encodes a protein containing homologous sequences to both a CX5R phosphatase and an ion channel. The authors named the novel protein, C. intestinalis voltage-sensor-containing phosphatase, Ci-VSP. The N terminus of Ci-VSP appears to function as a voltage-gated sensor; the C terminus functions as a phosphoinositide phosphatase. The authors suggest that when the N-terminal voltage sensor is activated, this in turn activates the phosphatase, which converts PI(3,4,5)P3 to PI(4,5)P2. Localized changes in membrane PI(4,5)P2 levels could then serve to either positively or negatively regulate a variety of ion transporters and channels.

  • Par-4, discovered in a screen for genes whose expression is increased in prostate tumor cells undergoing apoptosis, participates in physiological and pathological nerve cell death. A new study, however, provides evidence for an unexpected role for Par-4 in regulating synaptic transmission in the brain: Par-4 binds to the D2 dopamine receptor (D2DR) and modulates its activity. Mice in which the function of Par-4 is disrupted exhibit impaired dopaminergic neurotransmission, resulting in a depression-like syndrome. Several other cell death-related proteins also appear to function in regulating synaptic plasticity, suggesting that a better understanding of the functions of these proteins may lead to novel therapeutic approaches for a psychiatric and neurodegenerative disorders.


  • By the mid to late 1990s, the anorectic drug fenfluramine was prescribed to millions of patients annually, until the FDA announced withdrawal of the drug in 1997. Today, the epidemic of obesity calls ever more compellingly for new pharmacological therapeutics. But will it be possible to activate serotoninergic signaling in the brain (as did fenfluramine) without compromising cardiovascular health (as did fenfluramine)? One possibility for the selective targeting of obesity may be the serotonin 5-HT2C receptor, which appears to be associated with the signaling of satiety in energy-regulating centers in the brain. There are indications that selective activation of serotonin receptor subtypes may be possible, albeit difficult, and a variety compounds are under investigation in an effort to do so in the clinic.

  • Progressive neurodegenerative diseases are devastating conditions with a generally poor prognosis. Research in this field is exceptionally challenging, owing to the inherent complexity of the nervous system and the progressive nature of these diseases. Drosophila neurodegenerative mutants and transgenic flies recapitulate many key features of these diseases in vivo, including neural dysfunction and progressive neural cell loss. The authors summarize recent advances in our understanding of neurodegenerative disease mechanisms using the fly model and discuss the advantages and limitations of this system.

  • Migraine affects approximately eleven percent of adult populations in western countries. Unfortunately, our understanding of the biological mechanisms that underlie migraine continues to be incomplete, and in some cases, our mis-understanding of migraine may have distracted attempts to establish effective pharmacological therapies. Neurogenic inflammation has been a prime suspect in etiological investigations of migraine for decades, but it now appears that only some of the multiple signaling pathways that contribute to neurogenic inflammation are relevant to migraine. Experimental models of migraine must thus be chosen with care, as the success of therapeutic strategies may depend on targeting discrete aspects of neurogenic inflammation.

Beyond the Bench

Net Results