Structural insights into the dynamic process of G protein coupled receptor activationBrian Kobilka, MD Professor Department of Molecular and Cellular Physiology Stanford University School of Medicine Hélène Irwin Fagan Chair in Cardiology host: Stan Froehner abstract: G protein coupled receptors (GPCRs) conduct the majority of transmembrane responses to hormones and neurotransmitters, and mediate the senses of sight, smell and taste. The b2 adrenergic receptor (b2AR), the M2 muscarinic receptor and the mu-opioid receptor are prototypical Family A GPCRs. We have obtained three-dimensional structures of these receptors in inactive and active conformations, as well as a structure of the b2AR in complex with the G protein Gs. Comparison of these structures provides insights into common mechanisms for propagation of conformational changes from the agonist binding pocket to the G protein coupling interface. Crystal structures of inactive and active states may give the impression that GPCRs behave as simple two-state systems. However, cellular signaling assays reveal that many GPCRs signal through more than one G protein isoform, and through G protein independent pathways. This complex functional behavior provides evidence for the existence of multiple functionally distinct conformational states. We have used fluorescence, EPR and NMR spectroscopy to study the dynamic properties of several GPCRs. I will discuss what we these studies have taught us about allosteric regulation of GPCR structure by G proteins and ligands.
Molecular adaptations to the unique life style in mammalian hibernators.Elena Gracheva, PhD Associate Professor, Dept Cellular & Molecular Physiology, Dept Neuroscience Yale Abstract: Currently, the vast majority of cellular and molecular research in biological sciences focuses just on a handful of species, and even fewer are used as experimental models. In my lab, we have been developing non-standard animal models. We use hibernating 13-lined Ground squirrels (an obligatory hibernator) and Syrian hamsters (a non-obligatory hibernator), to tackle fundamental biological questions from perspectives unachievable using the standard animal models alone. Specifically, we are interested in studying molecular evolution of mammalian hibernation and cellular adaptations that these animals evolve in order to survive prolonged periods of hypothermia, water deprivation and starvation. We are also trying to pin point the molecular and physiological basis of hibernation induction. Comparative analysis of three rodent species—such as ground squirrels, hamsters and mice (non-hibernator)—at the behavioral, cellular and molecular levels, will help us to delineate the multitude of adaptations that hibernators evolved in order to survive harsh environment, and as a result came to inhabit a wide geographical range. host: John Tuthill
Ligand Recognition and Gating Mechanism of Temperature-sensitive TRPM2 channelJuan Du, Ph.D. Assistant Professor Department of Structural Biology, Van Andel Institute Abstract:
Body temperature is one of the most critical parameters indicating human health status. It is vital for mammals to detect the ambient temperature and to have the ability to regulate the internal temperature within a narrow range to prevent tissue damage. As hypo- or hyperthermia are associated with pathological conditions such as infection, inflammation, and cancer, body temperature is a primary parameter that is monitored in patients. The body temperature is precisely regulated by the hypothalamus, which serves as the principal thermostat that coordinates body temperature by employing a number of thermosensitive ion channel receptors. These ion channels mainly belong to the TRP (transient receptor potential) superfamily. My laboratory is broadly interested in how the human body detects and responds to environmental temperature via ion channel receptors and how the temperature is regulated to prevent tissue damage. In this talk, I will talk about our structural and functional studies of a warmth-activated TRP channel, TRPM2, using single-particle cryo-EM and patch-clamp electrophysiology. We defined a novel drug binding site in TRPM2 and our results revealed a ligand-driven activation and inhibition mechanism of TRPM2. This paves a solid foundation for our long-term goal – understanding of mechanism underlying temperature-induced activation of thermosensitive ion channels.host: Sharona Gordon
Action selection and action encoding during anxiety
Ruth Matarazzo Professor and Chair
Department of Behavioral Neuroscience
Oregon Health & Sci UnivThe prefrontal cortex (PFC) has been dubbed the “doer cortex” with a primary role of representing and selecting purposeful actions. In the context of psychiatric disorders, much of the neuronal data and computational work on the PFC encoding of behavior focuses on the representation (or perception) of internal and external events that precede these actions. We have been interested in the encoding of goal-directed actions per se by PFC neurons and how it is affected by anxiety. The focus on anxiety stems from the fact that its relevance to mental health extends well beyond anxiety disorders. Critically, anxiety is a debilitating symptom of most psychiatric disorders including PTSD, major depression, autism, schizophrenia and addiction. Anxiety is often studied as a stand-alone construct in laboratory animals that focuses on fear responses. But in the context of coping with real-life anxiety, its negative impacts extend beyond aversive feelings to involve disruptions in ongoing goal-directed behaviors and cognitive functioning. I will present data from two distinct models of anxiety that allowed us to perform ensemble and local field potential recordings during reward-guided goal-directed behaviors. We find that anxiety diminishes the recruitment of action encoding neurons and the coordinated activity between PFC and dopamine neurons. These results provide mechanistic insight for how anxiety diminishes rule-based guidance of behavior and single out encoding of actions, as opposed to cues or outcomes, by PFC neurons as particularly vulnerable to anxiety. host: Adrienne Fairhall
-joint sponsored with Department of Pharmacology-
Voltage-dependent but calcium-independent exocytosis of neurotransmittersZhuan Zhou, Ph.D.
Professor and Senior Investigator
Laboratory of Cellular Biophysics and Neurodegeneration
Institute of Molecular Medicine
Peking University, Beijing, P.R. CHINA
host: Bertil Hille