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.
Exploring the nature of spinal cord plasticity: Neurobiological mechanisms and implications for recovery after injuryPrior research has shown that pain (nociceptive) circuits within the spinal cord are affected by environmental relations and support some simple forms of learning (e.g., sensitization, instrumental conditioning). Further, learning can induce a modification in the capacity for learning (a form of metaplasticity); controllable stimulation enables learning through a process that depends upon brain derived neurotrophic factor (BDNF) while uncontrollable stimulation induces a lasting learning impairment that has been linked to the development of central sensitization and the cytokine tumor necrosis factor (TNF). I review data that show temporal predictability also affects spinal function by engaging an internal oscillator. Spinal injury disrupts descending serotonergic fibers that appear to quell nociceptive sensitization. This process is related to a change in the co-transporters that regulate spinal GABA function. It is also shown that nociceptive stimulation impairs recovery after a contusion injury. This effect is related to increased cell death and alterations in BDNF/TNF. Potential therapeutic treatments will be discussed.
Vocal motor control and sensorimotor learning: behavior, neurophysiology, and biomechanicsThe brain uses sensory feedback to calibrate the performance of complex behaviors. However, the neural and computational bases of sensorimotor learning remain mysterious. Our lab uses behavioral, physiological, biomechanical, and computational techniques to investigate the biological underpinnings vocal learning in songbirds. My talk will cover three ongoing lines of investigation into how songbirds correct vocal errors and precisely coordinate the acoustics of vocal production. First, our behavioral studies demonstrate that songbirds use vocal variability to constrain the speed and extent of vocal learning, and that the dynamics of learning across a number of experimental conditions can be understood as the result of an iterative process of Bayesian inference. Second, recent behavioral and anatomical studies demonstrate a crucial role for dopaminergic inputs to a basal ganglia nucleus in mediating vocal reinforcement learning. Third, neurophysiological recordings and computational analyses suggest that cortical motor neurons employ a millisecond-resolution spike timing code to regulate vocal behavior. Recent single-unit recordings from muscle tissue in behaving animals and in vitro measures of vocal biomechanics further suggest that millisecond-scale spike timing is an essential component of motor control, suggesting that reorganization of fine temporal spiking patterns might underlie vocal plasticity. Samuel J. Sober, Ph.D. Assistant Professor of Biology, Emory University Host: David Perkel
Examining neural circuits mediating social behaviors and motor learning using the CANE technologyFan Wang, Ph.D.Associate Professor, Department of Neurology Duke University
NMDA Receptors: learning from singles and beyondGabriela Popescu, PhD ProfessorDepartment of Biochemistry, Jacobs School of Medicine and Biomedical SciencesUniversity of Buffalo Popescu Laboratory Abstract NMDA receptors are members of the tetrameric ionotropic glutamate receptor family that fulfill unique and critical roles during the normal development and function of the central nervous system. These roles are supported by characteristic kinetic attributes of the glutamate-evoked output, which in turn reflect the receptor’s operation. In this talk, I will review the biologically salient features of the NMDA receptor response and describe recent mechanistic insights afforded by kinetic modeling of one channel currents. In addition, I will present unpublished data on novel modalities of gating host: Andres Barria
“Seven Transmembrane Receptors”Robert J. Lefkowitz, MD James B. Duke Professor of Medicine Investigator, Howard Hughes Medical Institute Duke University Medical Center Seven transmembrane receptors (7TMRs), also known as G protein coupled receptors (GPCRs) represent by far the largest, most versatile, and most ubiquitous of the several families of plasma membrane receptors. They regulate virtually all known physiological processes in humans. As recently as 40 years ago, the very existence of cellular receptors for drugs and hormones was highly controversial, and there was essentially no direct means of studying these putative molecules. Today, the family of GPCRs is known to number approximately 1,000, and crystal structures have recently been solved of approximately 25 members of the family and even of a receptor-G protein complex. In my lecture, I will briefly review how the field has evolved over the past 40 years, hanging some of the story on my own research throughout this period. Then I will discuss recent developments in the field, which are changing our concepts of how the receptors function and are regulated in fundamental ways. These include the duality of signaling through G-proteins and β-arrestins; the development of “biased ligands”; and the possibility of leveraging this new mechanistic and molecular information to develop new classes of therapeutic agents. Finally, I will discuss recent biophysical and structural studies of receptor-barrestin interactions.
Anastasios V. Tzingounis
University of Connecticut
Seizing the brake: defining the role of KCNQ2/3 channels in the brainMy seminar will focus on KCNQ channels, a potassium channel family implicated in multiple neonatal epileptic encephalopathy disorders. I will first discuss the role of KCNQ2/3 channels in interneurons. Previous research on the function of KCNQ2/3 channels nearly exclusively focused on excitatory neurons, but in fact these channels are also expressed by inhibitory interneurons. Insight regarding the function of KCNQ2/3 channels in interneurons has become critical as some newly identified epilepsy-associated KCNQ2/3 mutations have a gain-of-function effect on channel activity, and such mutations may lead to seizures through diminished inhibitory neuron activity. Second, I will present data regarding the molecular components that underlie the slow afterhyperpolarization (sAHP) in hippocampus and the role of KCNQ2/3 channels in the sAHP.
Host: Andres Barria
An ion channel on steroids: the unconventional pathway of calcium regulation by endogenous cannabinoidsPolina Lishko, PhD Assistant Professor of Cell and Developmental Biology Department of Molecular and Cell Biology UC Berkeley Host: Sharona Gordon Ion channels control sperm activity by regulating intracellular levels of calcium, which stimulates cell motility and fertility. Steroid hormone progesterone produced by an ovulated egg promotes the entry of calcium through sperm channel CatSper- an event so central for fertilization that men lacking these channels are infertile. We have demonstrated that human CatSper is associated with a membrane progesterone receptor, which makes human spermatozoa controlled by the female reproductive cycle. The identity of this receptor has been recently revealed to be serine hydrolase ABHD2 that degrades endogenous CatSper inhibitor 2-arachidonoylglycerol upon progesterone exposure. ABHD2 is ubiquitously expressed, and the pathway we have discovered in spermatozoa, is likely a universal pathway that defines membrane steroid signaling in other tissues.
Collective endothelial cell migration – cadherin fingers lead the wayArnold L. Hayer, Ph.D. Department of Chemical and Systems Biology Stanford University Abstract: The development and maintenance of the vasculature requires collective cell movement, during which neighboring cells coordinate the polarity of their migration machineries. We addressed the unresolved question of how polarity signals are transmitted from one cell to another across symmetrical cadherin junctions, using an in vitro model of collective endothelial cell migration. We found that collectively migrating endothelial cells have polarized VE-cadherin-rich membrane protrusions, ‘cadherin fingers’, which leading cells extend from their rear and follower cells engulf at their front. In follower cells, engulfment of cadherin fingers occurs along with the formation of a lamellipodia-like zone with low actomyosin contractility, and requires VE-cadherin/catenin complexes and Arp2/3-driven actin polymerization. Lateral accumulation of cadherin fingers in follower cells precedes turning, and increased actomyosin contractility can initiate cadherin finger extension as well as engulfment by a neighboring cell, to promote follower behavior. Cadherin fingers create positively curved membrane surfaces only in the front of follower cells, which selectively recruit and polarize curvature sensing regulatory proteins. Thus, engulfment of cadherin fingers at the cell front converts symmetric cadherin junctions into polarized structures that support collective cell guidance. Further, I will discuss our recent identification of a BAR domain and RhoGAP protein, which is required both for coordinated endothelial cell movement and vascular sprouting in vitro, and therefore establishes an intriguing mechanistic link between the asymmetric cadherin finger structure and RhoGTPase signaling. host: Stan Froehner
Couple, amplify, fire!
Coupling of L-type calcium channels and excitabilityL-type CaV1.2 and CaV1.3 calcium channels are key players in the generation and regulation of electrical activity in different cell types, including neurons and myocytes. In the pacemaker cells of the heart, the spike of the action potential that initiates each heartbeat depends entirely on the entry of calcium through these channels. Recently, we discovered a novel cooperative gating mechanism, on both CaV1.2 and CaV1.3 channels, which facilitates calcium entry and modulates the excitability of ventricular cardiomyocytes and neurons. We found that these channels establish a calcium-dependent physical interaction via their c-termini, which results in an increase in their open probability. Our more recent project aims to answer two new questions: Do CaV1.2 and CaV1.3 channel undergo functional coupling in the pacemaking cells of the heart? And, if so, is this coupling modulated by physiological stimuli? Our new results point to a mechanism by which beta-adrenergic signaling increases the coupling of CaV1.2 channels in the pacemaker cells. These exciting results add to our understanding on how the sympathetic nervous system increases heart rate. Claudia Moreno, Ph.D. Department of Physiology and Membrane Biology School of Medicine University of California, Davis host: Stan Froehner
How plants conquer the space: the cell’s flying plates
Plant cytokinesis is orchestrated by a specialized structure, the phragmoplast. The phragmoplast first occurred in representatives of Charophyte algae and then became the main division apparatus in land plants. Major cellular activities, including cytoskeletal dynamics, vesicle trafficking, membrane assembly, and cell wall biosynthesis, cooperate in the phragmoplast under the guidance of a complex signaling network. My research focuses on the self-organization processes that govern phragmoplast functions. I will give a general overview of plant cytokinesis, and present our recent data on the gamma-tubulin independent microtubule nucleation by the plant-specific protein MACERATOR and a conserved member of TPX2 protein family.Andrei Smertenko, Ph.D. Assistant Professor, Molecular Plant Sciences Washington State University host: Linda Wordeman