Table of Contents

Viewpoints

• • Gerald W. Zamponi and
  • Terrance P. Snutch

  Modulating Modulation: Crosstalk Between Regulatory Pathways of Presynaptic Calcium Channels

  Mol Interv December 2002 2:476-478; doi:10.1124/mi.2.8.476
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  The activity of some voltage-gated calcium channels (VGCCs) can be inhibited by specific G protein β subunits. Conversely, in the case of N-type VGCCs, protein kinase C can relieve G_β-dependent inhibition by phosphorylating at least one specific site on the calcium channel. A recent publication describes a newly identified method of intracellular regulation of specific VGCCs. Wu et al. have uncovered that VGCC activity can be regulated by phosphatidylinositol-4′,5′-bisphosphate (PIP₂ ). Whereas PIP₂ is important for maintaining the activity (open state) of Ca_v2.1 (N-type) and Ca_v2.2 (P/Q-type) channels, the enzymatic breakdown of PIP₂ leads to the inactivation of these channels. Additionally, PIP₂ can cause changes in voltage-dependent activation of Ca_v2.2 (P/Q-type) channels that make it more difficult for these channels to open (from the closed state). Furthermore, protein kinase A activity can circumvent PIP₂-mediated inhibition. Thus, the PIP₂-mediated regulation of VGCCs is tightly controlled by the functions of kinases (and phosphatases), as well as phospholipases. Wu et al. stress that because PIP₂ can be found at synapses, PIP₂-dependent control of VGCCs “could have profound consequences on synaptic transmission and plasticity.”

• • François Mach

  Toward a Role for Statins in Immunomodulation

  Mol Interv December 2002 2:478-480; doi:10.1124/mi.2.8.478
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  The family of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) inhibitors, collectively known as statins, is used clinically to reduce cholesterol levels in patients. Recent reports suggest that not only would statin therapy be beneficial for at-risk (genetically predisposed) people without symptoms of hypercholesterolemia, but that statins may have beneficial, pleiotropic effects in the treatment of autoimmune diseases. Youssef et al. have described how an HMG-CoA inhibitor, atorvastatin, might ameliorate experimental autoimmune encephalomyelitis (EAE), the mouse model for human multiple sclerosis. The possible clinical use of statins as anti-inflammatory drugs has also been demonstrated in other published reports. These provocative results suggest a role for statins in relieving autoimmune diseases such as multiple sclerosis.

• • Sheila A. Stewart

  Multiple Levels of Telomerase Regulation

  Mol Interv December 2002 2:481-483; doi:10.1124/mi.2.8.481
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  Normally, cell division leads to shortening of telomeres, the nucleoprotein complexes located at the ends of linear chromosomes. When telomeres reach a critically short length, cells cease to divide. However, immortal tumor cells display stable telomere lengths and are able to maintain their proliferative state. Wong and colleagues have found that telomerase is sequestered by nucleoli during certain stages of the cell cycle, decreasing the likelihood of telomerase access to chromatin until the late S phase. Additionally, they demonstrate that ionizing radiation tends to keep telomerase sequestered in nucleoli, whereas cell transformation leads to telomerase translocation into the nucleoplasm, where, presumably, it can catalyze the lengthening of telomeres at appropriate and inappropriate sites. The sequestration of telomerase thus imposes a newly identified level of regulation on telomerase activity, implicating telomerase localization as a potentially useful target for pharmacotherapy.