TMC function, dysfunction and the prospects for inner ear gene therapyJeffrey R. Holt, Ph.D. Associate Professor Department of Otolaryngology Harvard Medical School Holt/Geleoc Lab abstract: TMC proteins are of considerable interest for basic inner ear biologists and for translational and clinical neuroscientists because they cause deafness in mice and humans when mutated. Our research group has proposed they may be components of the elusive mechanotransduction channel in sensory hair cells. Evidence for and against this hypothesis will be presented. In addition, a potential gene therapy approach to restore hair cell and auditory function in mice and humans with Tmc1 mutations will be discussed. host: Ed Rubel
The spatial arrangement of a neuron’s synapses determines how inputs interact to perform computations, such as through recruitment of nonlinear conductances by spatially clustered activity. However, it remains poorly understood how such functional arrangements arise. We developed a random access microscope able to simultaneously record activity of every excitatory synapse, somatic firing, and dendrite morphology of an individual neuron throughout plasticity-inducing visual training in awake animals. We find that dendrite growth and pruning in the developing retinotectal system of transparent Xenopus tadpoles is regulated by sensory experience in a manner strongly dependent on each neuron’s evoked responses. We identify rules based on local dendritic activity patterns that promote clustering of synaptic inputs with shared tuning and promote processing of the specific stimuli experienced.Kurt Haas, Ph.D. Assistant Professor Brain Research Centre Department of Cellular and Physiological Sciences University of British Columbia lab website: http://www.haaslab.com/ Host: Andres Barria
L-type Ca2+ Channel Oligomerization in Hearts and MindsIn ventricular myocytes, excitation-contraction (EC) coupling occurs via a Ca2+ induced Ca2+ release mechanism such that the depolarization created by an action potential (AP) triggers Ca2+ influx through voltage-dependent L-type Ca2+ channels (i.e., Cav1.2 channels), which in turn stimulates further Ca2+ release from ryanodine receptors (RyRs) on the nearby junctional sarcoplasmic reticulum. The simultaneous activation of multiple RyRs across the myocyte results in a cell-wide increase in intracellular Ca2+ and triggers contraction. This process is remarkably reproducible despite the confounding fact that, at the membrane potential reached during the AP plateau, the driving force for Ca2+ entry through a single Cav1.2 channel is not sufficient to reliably activate RyRs. Instead it has been proposed that up to ten Cav1.2 channels must open simultaneously during the AP plateau to achieve this coupling fidelity. The mechanism that permits coordinated opening of multiple Cav1.2 channels during EC-coupling, however, has not yet been elucidated. Using electrophysiological, and optical approaches, we have found that an allosteric interaction between the C-terminal domains of voltage-gated CaV1.2 channels induces an increase in the open probability of the channels that amplifies Ca2+ influx during the AP and contributes to reproducible EC-coupling. We have also discovered that Cav1.3 channels that regulate excitability in neurons often display the same cooperative behavior. The objectives of this presentation are to summarize the molecular details of the channel interactions that we have resolved thus far and to highlight the significance of these findings to the cardiac and neuronal field Rose Dixon, Ph.D. University of Washington Chalk talk, Friday, January 22nd, at 9:30 in G-417.
A molecular mechanism of acute oxygen sensingWhile the molecular mechanism for slower adaptations to low oxygen (hypoxia) is known, mechanisms for rapid oxygen sensing are not well understood. Located at the bifurcation of the carotid artery in the neck, the mammalian carotid body is a chemosensory organ that senses decreases in blood oxygen to stimulate breathing within seconds. I will present the identification of an acute oxygen-sensing pathway in the mouse carotid body that senses hypoxia indirectly through detection of a metabolite. Andy J. Chang, PhD Stanford University Chalk Talk on Friday, February 5th, 9:30am in G-417.
Seminar Title: Thoughts (and Experiments) on Microtubule Nucleation
Abstract: Microtubules are born and reborn continuously, even during quiescence. These polymers are nucleated from templates, namely γ-tubulin ring complexes (γ-TuRCs) and severed microtubule ends. Interestingly, the rate of microtubule nucleation increases as cells enter mitosis, and all cells nucleate microtubules in distinct regions of their cytoplasms. How are these spatial and temporal profiles for microtubule nucleation established? I will discuss my lab’s recent attempts to answer this question using a mix of single-molecule biophysics, cell biology, and structural biology.
Host: Chip Asbury
The restricted and dynamically regulated subcellular localization of signaling proteins in highly differentiated cells such as mammalian neurons defines intra- and inter-cellular signaling events. Among neuronal proteins exhibiting the most highly compartmentalized expression are ion channels, whose localization at specific sites can both define signaling in that neuronal compartment, but also allow for discrete regulation of the population of channels found at these sites. I will describe the diverse mechanisms that establish, maintain and dynamically regulate ion channel expression at specific sites to support neuronal function and confer plasticity to neuronal signaling.