Table of Contents

October 2003; 3 (7)




  • The hormones glucagon and insulin delicately regulate the concentration of blood glucose. When patients become resistant to the effects of insulin or produce too little of it to properly regulate glucose concentrations, then diabetes can result. Unfortunately, not all patients with insulin-resistant, type 2 diabetes mellitus respond to drugs that improve insulin sensitivity. However, there is reason to be hopeful. A new molecule that targets glucokinase (GK), the enzyme responsible for phosphorylating glucose in pancreatic β cells and hepatic cells, acts to significantly reduce blood glucose concentrations in rodents. The GK activator RO-28-1675 increased the glucose affinity and Vmax of GK, and rats treated with RO-28-1675 had improved glucose tolerance and elevated glucose uptake in liver. These results provide the basis for improved drug design that may alleviate diabetes mellitus and the disorders that accompany it in patients.

  • Adenosine is known to participate in tissue protection subsequent to ischemic events. New evidence points to a role for adenosine in promoting neovascularization through a mechanism that requires interaction with the Toll-like receptor (TLR) signaling pathway. In macrophages, the adenosine receptor subtype 2A (A2AR) synergizes with some but not all of the Toll-like receptors, leading to increased expression of vascular endothelial growth factor (VEGF). Simultaneously, the expression of tumor necrosis factor–α (TNFα) is decreased; this phenomenon depends on the presence of AR agonists; however, the activation of transcription factor nuclear factor–κB (NF–κB) is not attenuated in the presence of A2AR agonists. It appears that the addition of adenosine or other A2AR agonists can mediate the “angiogenic switch,” in macrophages, from TNFα protein expression to expression of components necessary for angiogenesis. Although these observations might have important implications for wound healing, it will be important to discern whether this interaction between ARs and TLRs is necessary for angiogenesis associated with tumor growth.


  • Key to the processes of learning and memory is the concept of synaptic plasticity. Synapses form and dissociate depending upon reinforcement of established synapses. Because α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptors mediate much of the excitatory signaling in the brain, it is not surprising that the presence of these receptors is important to the plastic process of neuron–neuron communication. AMPA receptors shuttle to and from synapses through a combination of constitutive and regulated pathways. Great strides have been made in understanding the processes underlying synaptic plasticity.

  • How do cells regulate the activities of ubiquitous kinases that use many different substrates? In neurons, calcium-calmodulin–dependent protein kinase II (CaMKII) participates in regulating neuronal and behavioral plasticity, but how is this regulator regulated? Different isozymes, alternatively spliced variants, and the use of differing combinations of phosphorylation sites create many different versions of CaMKII that are localized to different subcellular compartments associated with discrete CaMKII functions. Additionally, different forms of CaMKII can associate with different binding proteins, which may further specify the location in time and space of CaMKIIs in the neuron, leading to changes in synapses.

  • Repetition has long been accepted as an important, if somewhat laborious, pedagogical device. The replay of neuronal events that occur during learning is now recognized as an important function of sleep, and the extinction of neuronal activity that is no longer relevant to new learning tasks may be similarly regarded as an active function of the brain "at rest." The systems and techniques that are now available for sleep researchers are yielding new insights into brain function and neuronal plasticity. The classically known characteristics of the sleeping brain, as established by electroencephalography, also prove to be influenced in specific ways by waking experience. An understanding of the reciprocal relationship between sleep and experience may lead to therapeutics that not only alleviate sleep disorders per se, but that may also facilitate learning itself.

Beyond the Bench