Table of Contents

February 2004; 4 (1)

Speaking of Pharmacology




  • Of the ten mammalian voltage-gated calcium channels (VGCCs), those belonging to the L-type family have been best studied for the development of useful therapeutics for hypertension. Other studies on drugs that target the T-type family of VGCCs suggest that T-type channels might also be relevant to clinically directed modulation of hypertension; however, the selectivity of one such drug (i.e., mibefradil) has been called into question. CacnaH1 encodes Cav3.2, one of the three T-type channels. Recently, Cacna1H−/− mice were developed to ascertain the normal roles of T-type channels. Cav3.2-null mice possess continually constricted arterioles in the heart. The smooth muscle and arterioles from isolated knockout mice are able to contract normally in vitro; however, in the presence of acetylcholine (ACh) or other relaxing agents, the mutant vasculature is unable to relax to the same degree as does wild-type vasculature. Similarly, blocking wild-type T-type channels prevents ACh-mediated relaxation. These results suggest an important role of T-type channels in normal cardiovascular function. But is hope for a specific and useful T-type channel–targeted drug premature?

  • When it comes to studying elephants with microscopes, it is helpful, occasionally, to take a few steps back to remind oneself that the whole beast is greater than the sum of its parts. Perhaps the same is true for serotoninergic neurons. In the medulla, serotoninergic neurons function as chemoreceptors. New research indicates that serotoninergic neurons in the midbrain raphe are sensitive to CO2 concentrations in the blood. Severson and colleagues have suggested that serotoninergic neurons located throughout the brainstem share a similar function: the regulation of systemic pH homeostasis. Most intriguing is the supposition that the dysfunction of these medullary and midbrain serotoninergic neurons might lead to migraine headaches, anxiety or panic disorder, or lack of arousal leading to suffocation, or in the case of infants, sudden infant death syndrome (SIDS).


  • Cognitive processes require the proper function of cholinergic neurons, as does signal transmission at neuromuscular junctions. Indeed, the increased synthesis and output of acetylcholine (ACh) can ameliorate diseases involving impaired cholinergic activity. Once released into the synapse, ACh is quickly hydrolyzed, thus terminating the ACh activation of postsynaptic receptors. Further release of ACh requires the reuptake of choline, mediated by the choline transporter (CHT) at presynaptic neurons, which is the rate-limiting step in the production of acetylcholine. Subsequent to choline reuptake, ACh is efficiently produced by choline acetyltransferase and put into synaptic vesicles by the vesicular ACh transporter. Knowing how CHT function is regulated may lead to intelligently designed interventions to mitigate deficient cholinergic function.

  • The protein–protein interactions that underlie the functions of a variety integral membrane proteins are becoming increasingly appreciated for their relevance to signal transduction pathways. It now appears that the sodiumdependent reuptake of synaptic neurotransmitters is also a system where the oligomerization of membrane polypeptides (i.e., of the sodium-dependent neurotransmitter transporters) has proven essential to protein functionality. In some instances, oligomerization appears to be crucial to the trafficking of transporter proteins prior to their localization within the plasma membrane. These new insights have implications in the treatment of psychoneurological disorders, and may moreover underscore oligomerization as a quality control mechanism in vesicular packaging and secretory pathways.

  • The fact that protein kinases regulate the enzymatic activities of many proteins is nothing new; however, in the case of protein kinase C (PKC)–mediated regulation of glutamate transport, the complexities of control (activation and attenuation) suggest a previously underappreciated mechanism by which disposition of this ubiquitous neurotransmitter might be controlled. PKC directly or indirectly regulates the transcription, membrane trafficking, and possibly the intrinsic activity of many glutamate transporter subtypes. It appears that PKC has differential effects on neuronal and glial glutamate transporters, increasing the activity a neuronal transporter and decreasing the activity of a glial transporter. Finally, many of these effects may depend on accessory proteins and the array of PKC isozymes present in any given cell type. The ability to remodel glutamate clearance within minutes may provide a mechanism that complements the dynamic changes in glutamate receptor function that are thought to accompany learning and memory.

Beyond the Bench

Net Results