ENGLISH Pasaje Harrington 287 CENTRO Playa Ancha Valparaíso, Chile INTERDISCIPLINARIO +56 32 2508040 DE NEUROCIENCIA UNIVERSIDAD DE VALPARAÍSO WWW.CINV.CL RESEARCH LINES RESEARCH LINE 1 STRUCTURE AND FUNCTION OF MOLECULAR SELECTED PUBLICATIONS SENSORS Qiu F, Rebolledo S, González C, Larsson HP (2013). Subunit interactions during cooperative opening of voltage-gated This line of research aims to reveal mechanisms that proton channels. Neuron. 77(2):288-98. lead to ion channel opening in response to stimuli such as changes in electric potential, intracellular calcium concen- Pantazis A, Savalli N, Sigg D, Neely A, Olcese R (2014). tration or environmental temperature. At present we are Functional heterogeneity of the four voltage sensors of a attempting to answer the following questions: (a) Is there human L-type calcium channel. Proc. Natl. Acad. Sci. USA. a temperature sensor in transient receptor potential (TRP) 111(51):18381-6. channels? And if so, (b) what is its molecular nature? and (c) How the electrical, chemical or thermal energy is Raddatz N, Castillo JP, González C, Alvarez O, Latorre transformed into mechanical energy (the pore opening)? R (2014).Temperature and voltage coupling to channel In order to answer these questions we are using electro- opening in transient receptor potential melastatin 8 physiological (voltage clamp y patch clamp), fluorescence (TRPM8). J Biol Chem. 289(51):35438-54. (Selected as JBC (lanthanide resonance energy transfer –LRET- and volt- paper of the week). age-controlled fluorometry-VCF), and molecular modeling techniques (together with research line 5). Our research- Pupo A & González C (2014). In pursuit of an inhibitory ers have carried out studies on the functioning of voltage drug for the proton channel (Hv1). Proc. Natl. Acad. Sci. sensors in proton channels (Hv), in voltage- and Ca2+-ac- USA. 111(27):9673-74. tivated K+ channels, in voltage-dependent Ca2+ channels, and in connexins. They have succeeded in detecting gating Jabba S, Goyal R, Sosa-Pagán JO, Moldenhauer H, Wu J, currents in Hv and movements of an extracellular domain Kalmeta B, Bandell M, Latorre R, Patapoutian A, Grandl J in a connexin (Cx) by using VCF (together with research (2014). Directionality of Temperature Activation in Mouse line 2). They have also found that the TRPM8 channel (a TRPA1 Ion Channel Can Be Inverted by Single-Point cold receptor) can be opened only by decreasing tempera- Mutations in Ankyrin Repeat Six. Neuron. 82(5):1017-1031. ture through a temperature-independent pathways and we have identified the molecular nature of the phophati- Castillo, JP, Rui H, BasilioD, Roux B, Latorre R, Bezanilla dylinositol 4,5-biphosphate binding site in TRPV1 channel F and Holmgren M (2015). Mechanism of potassium ion (a heat receptor). uptake by Na+/K-ATPase. Nature Comm. July 24 6:7622 PRINCIPAL INVESTIGATORS Diaz-Franulic I, Poblete H, Miño G, González C and Latorre R (2016). Allosterism and Structure in Thermally Ramón Latorre, Alan Neely, Carlos González. Activated Transient Receptor Potential Channels Ann. Rev. Biophys. 45:371-398 co-investigatoRs Francisco Bezanilla (University of Chicago), Miguel Holmgren (NIH, USA), Osvaldo Alvarez Pinto BI, García IE, Pupo A, Retamal MA, Martinez AD, (Universidad de Chile), Peter Larsson (University of Mia- Latorre R and Gonzalez C (2016). Charged residues at mi), Luis Cuello (Texas Tech University), Riccardo Olcese the first transmembrane region contribute to the voltage (University of California at LA). dependence of connexins slow gate. J Biol Chem 291:15740-52 ENGLISH Pasaje Harrington 287 CENTRO Playa Ancha Valparaíso, Chile INTERDISCIPLINARIO +56 32 2508040 DE NEUROCIENCIA UNIVERSIDAD DE VALPARAÍSO WWW.CINV.CL RESEARCH LINES RESEARCH LINE 2 CELL SIGNALING This line studies the molecular mechanisms underly- Schalper KA, Palacios-Prado N, Retamal MA, Shoji KF, ing cell signaling. By combining molecular, electrophysi- Martínez AD, Sáez JC (2008). The connexin hemichannel ological, molecular dynamics and fluorescence techniques, composition determines the FGF-1-induced membrane our researchers have shed light on the following issues: (1) permeability and free Ca2+i responses. Mol Biol Cell 19(8): the molecular structures involved in oligomerization and 3501–3513. function of connexins 26 and 43, which form hemichan- nels and gap junction channels. These channels mediate González-Jamett AM, Momboisse F, Haro-Acuña intercellular communication pathways, and some muta- V, Bevilacqua JA, Caviedes P, Cárdenas AM (2013). tions in their coding genes can cause syndromic and non- Dynamin-2 function and dysfunction along the secretory syndromic deafness. (2) In the brain, we studied the role of pathway. Front Endocrinol 4:126. connexin hemichannels in inflammatory responses of neu- rodegenerative diseases; (3) new roles of pannexin chan- Jara O, Acuña R, García IE, Maripillán J, Figueroa V, Sáez nels in cellular communication, synaptic plasticity, neural JC, Araya-Secchi R, Lagos CF, Perez-Acle T, Berthoud excitability, neurosecretion, and potentiation of skeletal VM, Beyer EC, Martínez AD (2012). Critical role of muscle contraction. (4) We also studied dynamin-2, a GT- the first transmembrane domain of Cx26 in regulating Pase responsible for endocytosis, in controlling cortactin oligomerization and function. Mol Biol Cell 23(17):3299- dynamics during the process of transmitter release as well 3311. as mutations in dynamin-2, which cause myopathies, on the intercellular transport of proteins needed for skeletal González-Jamett AM, Momboisse F, Guerra MJ, Ory muscle metabolism. S, Báez-Matus X, Barraza N, Calco V, Houy S, Couve E, Neely A, Martínez AD, Gasman S, Cárdenas AM (2013). PRINCIPAL INVESTIGATORS Dynamin-2 regulates fusion pore expansion and quantal release through a mechanism that involves actin dynamics Juan Carlos Sáez1, Ana María Cárdenas, Agustín Martínez. in neuroendocrine chromaffin cells. PLoS One 8(8):70638. young investigatoR Helmut Sánchez. García IE, Maripillán J, Jara O, Ceriani R, Palacios-Muñoz A, Ramachandran J, Olivero P, Perez-Acle T, González C, SELECTED PUBLICATIONS Sáez JC, Contreras JE, Martínez AD (2015). Keratitis- ichthyosis-deafness syndrome-associated Cx26 mutants Cea LC, Cisterna BA, Puebla C, Frank M, Figueroa XF, produce nonfunctional gap junctions but hyperactive Cardozo C, Willecke K, Latorre R, Sáez JC (2013). De hemichannels when co-expressed with wild type Cx43. J novo expression of connexin hemichannels in denervated Invest Dermatol 135(5): 1338-47. fast skeletal muscles leads to atrophy. Proc Natl Acad Sci USA 110(40):16229-16234. 1 Investigator from the Pontificia Universidad Católica de Chile (PUC). ENGLISH Pasaje Harrington 287 CENTRO Playa Ancha Valparaíso, Chile INTERDISCIPLINARIO +56 32 2508040 DE NEUROCIENCIA UNIVERSIDAD DE VALPARAÍSO WWW.CINV.CL RESEARCH LINES RESEARCH LINE 3 GENETICS AND NEURAL SYSTEM DEVELOPMENT Researchers in this line have shown that, in early de- (2015). Zebrafish adult-derived hypothalamic neurosphe- velopment, environmental odors can inhibit the expres- res generate gonadotropin-releasing hormone (GnRH) sion of olfactory receptors, and are currently exploring the neurons. Biol Open. 4(9):1077-86 mechanisms underlying this epigenetic interaction. They have found that adult stem cells can generate endocrine Torres-Paz J and Whitlock K.E. (2014). Olfactory sensory cells that are essential during puberty. This observation system develops from coordinated movements within the was made by using the zebrafish as a model system, and led neural plate. Dev Dyn. 2014 Dec;243(12):1619-31. to the initiation of a joint collaboration to analyze the genes involved in Kallmann syndrome. Toward gaining a better Diao F, Mena W, Shi J, Park D, Diao F, Taghert P, Ewer J understanding of how neuropeptides regulate expression and White BH (2016). The Splice Isoforms of the Droso- in sequential behavior, researchers have genetically coded phila Ecdysis Triggering Hormone Receptor have develop- Ca2+ markers in Drosophila. They have also gained great- mentally distinct roles. Genetics. 202(1): 175-189. er insight into how the circadian clock imposes a daily rhythm on behavior. A new research line is exploring how Krüger E, Mena W, Lahr EC, Johnson EC and Ewer J environmental parameters and diet such as the presence or (2015). Genetic analysis of Eclosion hormone action du- absence of food, and the presence of specific foods, change ring Drosophila larval ecdysis. Development. 142(24): 4279- animal’s behavior. Currently, the group is working on iden- 4287. tifying discrete elements of diet that provoke a change in behavior and the molecular targets in the host that change Diao F, Ironfield H, Luan H, Diao F, Shropshire WC, Ewer their expression to bring about the behavioral change. To J, Marr E, Potter CJ, Landgraf M and White BH (2015). this end, they use C. elegans as a model organism employ- Plug-and-Play Genetic Access to Drosophila Cell Types ing strategies that include functional genomics, behavioral using Exchangeable Exon Cassettes. Cell Rep. 10(8): 1410- assays, molecular and cellular techniques and OMICS ap- 1421. proaches. Lahr EC, Dean D, Ewer J (2012). Genetic analysis of ecdy- PRINCIPAL INVESTIGATORS sis behavior in Drosophila reveals partially overlapping functions of two unrelated neuropeptides. J. Neurosci. Kathleen Whitlock, John Ewer, Andrea Calixto1. 32(20): 6819-29. SELECTED PUBLICATIONS Calixto A. (2015) Life without food and the implications for neurodegeneration. Advances in Genetics, Volume 92.