1. TRPV1 Antagonists to Warm the Soul
Narender R. Gavva, Anthony W. Bannon, Sekhar Surapaneni, David N. Hovland Jr, Sonya Lehto, Anu Gore, Todd Juan, Hong Deng, Bora Han, Lana Klionsky, Rongzhen Kuang, April Le, Rami Tamir, Jue Wang, Brad Youngblood, Dawn Zhu, Mark H. Norman, Ella Magal, James J. S. Treanor, and Jean-Claude Louis
For pain-sensing neurons, the vanilloid receptor TRPV1 is a jack-of-all-trades being activated by heat, acid, and capsaicin. This week, Gavva et al. show that TRPV1 is also tonically active as manifested by an increase in body temperature after antagonist administration. The authors treated rats with the TRPV1 antagonist (E)-3-(4- t-butylphenyl)-N-(2,3-dihydrobenzo[b] [1,4]dioxin-6-yl)acrylamide (AMG9810), which blocked hypothermia induced by capsaicin. However, AMG9810 also increased body temperature by 1¡ãC within 30 minutes. A variety of TRPV1 antagonists had the same effect, indicating that a sub-modality-specific block was not responsible. The hyperthermia was mediated in the periphery, occurred in multiple species including primates, and correlated with block of either capsaicin or heat activation of the channel. Because TRPV1 agonists like capsaicin cause hypothermia, these results suggest that tonic activity of TRPV1 is involved in body temperature regulation. TRPV1 antagonists may warm the soul of subjects, but perhaps not those trying to design compounds to treat chronic pain.
2. Rho, Endocytosis, and Oligodendroglial Membrane Growth
Angelika Kippert, Katarina Trajkovic, Lawrence Rajendran, Jonas Ries, and Mikael Simons
When forming myelin, oligodendrocytes have a big job in creating all that membrane. Specialized proteolipid protein (PLP) components of myelin membranes are expressed in the absence of neurons, but an unknown diffusible neuronal factor triggers a switch in PLP trafficking. This week, Kippert et al. investigated the trafficking of PLP from late endosomes/lysosomes (LEs/Ls) to the plasma membrane. The authors used Oli-neu cells, an oligodendroglial line stably expressing fluorescently labeled PLP (PLP-EGFP). Conditioned media from primary neuronal cultures triggered cell differentiation and PLP-EGFP redistribution. Inhibition of tyrosine kinases or Rho GTPase also triggered PLP-EGFP movement, and the addition of neuronal-conditioned medium reduced RhoA activity. In immature oligodendrocytes, Rho mediated clathrinin-independent endocytosis, but upon differentiation, Rho activity and the endocytotic pathway were downregulated in favor of LE/L vesicle mobilization. The authors propose that endocytosis is a control point for the massive requirement for membrane in myelin.
3. Flash Stimulation of the Circadian Visual System
Luis Vidal and Lawrence P. Morin
The mammalian ¨¹ber-clock in the supra-chiasmatic nucleus (SCN) sets the circadian rhythm based on photic input received over the day/night cycle. Resetting the clock with light stimulation occurs after continuous pulses, in which phase shifts result from integration or "photon counting" of long, relatively dim light pulses. However, as Vidal and Morin show this week in hamsters, brief trains of millisecond-long intense light flashes can cause significant phase shifts. Hamsters exposed to as few as three 2 ms light flashes over a 5 min or even a 60 min period displayed nearly all-or-none phase shifts, although 10 or more flashes produced more consistent and robust results. The shifts required an irradiance threshold of 140 ¦ÌW/cm2, an interflash interval of not shorter than a few seconds, and were accompanied by increases in the immediate early gene FOS in the SCN and beyond. Might be good news for jet-lag sufferers.
4. Osteopontin and Spinal Cord Injury
Masayuki Hashimoto, Dongming Sun, Susan R. Rittling, David T. Denhardt, and Wise Young
The chemokine osteopontin (OPN) is expressed by microglia as part of inflammatory responses. Although suppression of OPN results in a better outcome in animal models of autoimmune disease, Hashimoto et al. report this week that OPN may be neuroprotective in spinal cord injury. The authors compared the effects of a spinal cord contusion at T13 in wild-type (WT) and OPN-deficient [knock-out (KO)] mice. At 24 h after contusion, the proinflammatory cytokines TNF (tumor necrosis factor)-¦Á, interleukin (IL)-1 ¦Â, and IL-6 were downregulated in KO spinal cords according to quantitative real-time PCR, but protein levels were not significantly reduced at 7 d after injury. Both mRNA and protein levels of the antiapoptotic Bcl-2 were reduced in KO mice. The KO mice performed worse in a locomotor assay 6 weeks after injury and also showed reduced areas of white matter sparing and fewer neurons surrounding the site of impact.