The Spice Ain't Always So Nice; Three Methyls and You're Out; Interdisciplinary Research

The Spice Ain't Always So Nice Anne Macnamara Capsaicin, the fiery alkaloid of chili pepper fame, sets tongue and skin afire, a sensation that some find irresistible. But, researchers recently associated it and its chemical cousins with chest pain.1 Isolated more than a century ago, capsaicin's structure was revealed in 1919, and its target, the vanilloid receptor 1 (VR1), was cloned in 1997. "VR1 functions as a molecular integrator of painful chemical and physical stimuli, including heat and low pH, such as [in] tissue acidosis caused by ischemia," explains team leader Hui-Lin Pan, professor of anesthesiology at the Pennsylvania State University College of Medicine. Because capsaicin applied to animal hearts increases blood pressure, the researchers hypothesized that VR1 receptors might be in the heart. They applied a potent capsaicin analog, resiniferatoxin, to rat hearts, destroying nerve endings in the heart's outer layer. Capsaicin no longer raised blood pressure nor, presumably, caused chest pain. The new work elevates the receptor's role from what Harold Schultz, physiology professor at the University of Nebraska Medical Center, calls a "pharmacological curiosity" to an important conduit in the response to ischemia. The finding may explain silent ischemia, a condition in which people do not feel pain, even when their hearts are starved for oxygen. Their blockages may be deep, out of the receptors' reach, Pan suggests. He foresees drugs that will plug the receptors, treating angina unresponsive to nitroglycerin. --Ricki Lewis 1. M.R. Zahner et al., "Cardiac vanilloid receptor 1-expressing afferent nerves and their role in the cardiogenic sympathetic reflex in rats," J Physiol, 551:515-23, September 2003. Interdisciplinary Research These papers were selected from multiple disciplines from the Faculty of 1000, a web-based literature awareness tool (www.facultyof1000.com). R.J. Pasterkamp et al., "Semaphorin 7A promotes axon outgrowth through integrins and MAPKs," Nature, 424:398-405, July 24, 2003. "A membrane-tethered member of the semaphorin family of repulsive guidance proteins, Sema7A, is shown to have an unexpected axon growth-promoting function. This function is not mediated by the canonical Sema7A receptor, plexinC1, but rather by B1-integrins through the MAPk signaling pathway. Integrin-mediated semaphorin signaling may be a general mechanism used in nervous system development and in immune system function." --Ruediger Klein, Max Planck Institute of Neurobiology, Germany T.S. Tang et al., "Huntingtin and huntingtin-associated protein 1 influence neuronal calcium signaling mediated by inositol-(1,4,5) triphosphate receptor type 1," Neuron, 39:227-39, July 17, 2003. "The authors provide a link between Huntington disease and calcium signaling by demonstrating that huntingtin, particularly when it includes polyglutamine repeats, regulates inositol 1,4, 5-triphosphate (IP3) receptors. They demonstrate a weak, direct interaction between IP3 receptors and huntingtin, and a much stronger interaction mediated by huntingtin-associated protein 1A (HAP1A) that is strongest when the huntingtin includes the polyglutamine expansion." --Colin Taylor, University of Cambridge, UK O. Micheau, J. Tschopp, "Induction of TNF receptor I-mediated apoptosis via two sequential signaling complexes," Cell, 114:181-90, July 25, 2003. "[The paper] demonstrates that the signaling by TNF receptor 1 (TNFR1) involves two sequential signaling complexes ... Activation of NF-kB by complex 1 results in recruitment of FLIP ... to complex 2 and cell survival; otherwise activation of caspase-8 in complex 2 leads to apoptosis. Thus, the two complexes act as checkpoints to regulate TNF-mediated cell survival and apoptosis. When complex1-initiated NF-kB activation fails, cells undergo apoptosis via complex 2." --Sharad Kumar, Institute of Medical and Veterinary Science, Hanson Centre for Cancer Research, Australia Three Methyls and You're Out Courtesy of Sean D. Taverna, University of Virginia Researcher Yi Zhang at the University of North Carolina, Chapel Hill, and others recently upped the complexity of gene silencing with the discovery of mAM, the murine ATFa-associated modulator. Changes in gene expression can be controlled by factors outside the genetic code, such as chromatin structure. One of these so-called epigenetic mechanisms, histone methylation, has been implicated in gene silencing. These signals, orchestrated by histone methyltransferases (HMTases), occur on both lysine and arginine residues. Zhang previously identified ESET, an HMTase in mice that adds one or two methyl groups to the ninth lysine (K9) of histone H3. But mono- and dimethylation produce only gene repression: Genes are transcribed but in limited quantities. Complete silencing, according to Zhang's findings, requires trimethylation, which is facilitated by an ESET/mAM complex.1 Their human homologs, SETDB1 and hAM, form a similar complex to achieve trimethylation. Though it is not clear what genes these trimethyl signals affect, cells die when both ESET and mAM are removed. This suggests a putative role for affected genes in apoptosis, says Zhang. It's a first example of an HMTase subunit modulating the complex's activity, explains Manel Esteller, of the Spanish National Cancer Center in Madrid, in an E-mail. "The challenge now is to identify novel subunits that direct these complexes to specific genomic sites or modulate interactions with specific transcription factors." --Maria W. Anderson 1. H. Wang et al., "mAM facilitates conversion by ESET of dimethyl to trimethyl lysine 9 of histone H3 to cause transcriptional repression," Mol Cell, 12:475-87, August 2003. function sendData() { document.frm.pathName.value = location.pathname; result = false if (document.frm.score[0].checked) result = true; if (document.frm.score[1].checked) result = true; if (document.frm.score[2].checked) result = true; if (document.frm.score[3].checked) result = true; if (document.frm.score[4].checked) result = true; if (!result) alert("Please select") return result; } .myradio{background-color : #94bee5} Please indicate on a 1 - 5 scale how strongly you would recommend this article to your colleagues? Not recommended 1 2 3 4 5 Highly recommended Please register your vote

The Spice Ain't Always So Nice; Three Methyls and You're Out; Interdisciplinary Research

Interested in reading more?

Become a Member of