Research Report 2010 - MDC

Structure of the GroupJan Siemens(Sofia Kovalevskaya Prize)Group LeaderDr. Jan Siemens**Graduate StudentsChristina Hanack*Kun Song*Technical AssistantsJana Rossius*SecretariatManuela Brandenburg**part of the period reported** start of the group: May 2009Sensory NeurobiologyThe ability of any living organism to probe and sense stimuli emanating from thesurrounding environment is of fundamental importance for its well-being and survival.While a lot of progress has been made in elucidating sensory systems such as vision andolfaction, our understanding of the somatosensory system, giving rise to the detection of(painful) mechanical stimuli as well as changes in temperature, is lacking behind.Sensory mechanisms not only monitor the outside world but also detect changes of interiorparameters such as blood sugar levels, osmolarity, body temperature and many others.Processing and integration of sensory information from the outside world and the interiorenvironment allows our body to maintain homeostasis.Our research focuses on understanding sensory mechanisms at the molecular level.Previous WorkAs a postdoctoral fellow in the lab of David Julius at theUniversity of California San Francisco, I focused on thermo-sensoryion channels of the pain pathway. My projectshave centered on describing new pharmacologicaltools to study and manipulate these ion channels andon genetic methods to determine their physiologicalroles in vivo.Bites and stings from venomous creatures can producepain and inflammation but little is known of howvenom ingredients activate the pain pathway. In thesomatosensory system, sensors for painful (and thermal)stimuli include the TRP channel family membersTRPV1, TRPM8, and TRPA1. I found that three inhibitorcystein knot (ICK) peptides from tarantula venom targetTRPV1, the capsaicin receptor. In contrast to the predominantrole of other ICK toxins as channel inhibitors,these newly discovered toxins -termed vanillotoxinsfunctionas TRPV1 agonists, which explains how venomscan cause pain. Moreover, these toxins constitute newpharmacological tools to study TRP channel gating andgenerate drugs that block the pain pathway.TRPM8 is activated by menthol, a product of the mintplant used in chewing gum and toothpaste to evoke acooling sensation. Low temperatures activate TRPM8 invitro, further suggesting that TRPM8 is a cold receptor.To test this hypothesis in vivo, we generated TRPM8deficient mice and examined their response to coldstimuli. We found that these mice were not able to discriminatebetween cold and warm temperatures inbehavior assays and displayed dramatically reducedresponses to cold stimuli at the cellular level. Thesefindings validate the hypothesis that TRP channels participatein the sensation of thermal stimuli in theperipheral nervous system.TRPA1 is a detector of environmental irritants such asacrolein, an airway irritant present in tear gas, vehicleexhaust and smoke. We found that 4-Hydroxynonenal(HNE), a molecule produced in response to tissue injury,is a potent activator of TRPA1, demonstrating that thision channel is also an important sensor for endogenousinflammatory factors.In summary, my postdoctoral studies have advancedour understanding of TRP channel function in inflammationand peripheral temperature sensation.172 Function and Dysfunction of the Nervous System