Ion channel activity at the nerve terminal determines presynaptic action potential shape and Ca2+ entry and thus plays a pivotal role in the regulation of synaptic transmission. This is particularly important in the presynaptic terminals of the neocortex, due to this brain region's role in mediating higher neurological function under normal conditions and during disease states. We have recently developed a technique that permits electrophysiological recording from single, acutely isolated rat neocortical nerve terminals. The long-term objective of the laboratory is to answer questions about the physiological and pathophysiological regulation of synaptic transmission by directly studying neocortical, presynaptic ion channels with this technique. An increase in intracellular [Ca2+] ([Ca2+]i) is a critical signal at the synapse where it triggers exocytosis, plasticity and gene expression. Much more is known about signaling downstream of changes in intracellular Ca2+ than about the impact of changes in extracellular [Ca2+] ([Ca2+]o). Yet [Ca2+]o is likely to undergo significant changes as a result of electrical activity. The driving hypothesis for this proposal is that a decrease in synaptic cleft [Ca2+] is an important signal which regulates synaptic efficacy. We have recently discovered a novel, Ca2+-based signaling pathway in neocortical nerve terminals, comprised of a voltage sensitive non-specific cation (NSC) channel activated by decreases in [Ca2+]o. This interesting finding poses a number of questions: what is the mechanism by which changes in [Ca2+]o are detected and transduced to alterations in membrane conductance? Is the Ca2+ sensor-NSC channel signaling pathway modulated by other agents at the nerve terminal? What is the physiological impact of Ca2+ sensor-NSC channel signaling pathway on synaptic transmission? To answer these questions we plan to use a combination of electrophysiological, pharmacological and immunochemical techniques to: 1. Identify the constituents of the Ca2+ sensor-NSC channel signaling pathway. 2. Determine physiological modulators of Ca2+ sensor-NSC channel signaling pathway. 3. Determine the role of the Ca2+ sensor-NSC channel signaling pathway in synaptic transmission. The goals of this proposal are to understand the mechanism by which [Ca2+]o modulates ion channel activity in the synapses of the cortical nerve terminals and to determine how this Ca2+ sensor-NSC channel signaling pathway impacts synaptic transmission in the neocortex.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS043444-03
Application #
6890968
Study Section
Special Emphasis Panel (ZRG1-MDCN-4 (01))
Program Officer
Talley, Edmund M
Project Start
2003-05-15
Project End
2007-04-30
Budget Start
2005-05-01
Budget End
2006-04-30
Support Year
3
Fiscal Year
2005
Total Cost
$251,038
Indirect Cost
Name
Oregon Health and Science University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
Williams, Courtney L; Smith, Stephen M (2018) Calcium dependence of spontaneous neurotransmitter release. J Neurosci Res 96:335-347
Vyleta, Nicholas P; Smith, Stephen M (2011) Spontaneous glutamate release is independent of calcium influx and tonically activated by the calcium-sensing receptor. J Neurosci 31:4593-606
Jin, Y-H; Cahill, E A; Fernandes, L G et al. (2010) Optical tracking of phenotypically diverse individual synapses on solitary tract nucleus neurons. Brain Res 1312:54-66
Chen, Wenyan; Bergsman, Jeremy B; Wang, Xiaohua et al. (2010) Presynaptic external calcium signaling involves the calcium-sensing receptor in neocortical nerve terminals. PLoS One 5:e8563
Harnett, Mark T; Chen, Wenyan; Smith, Stephen M (2009) Calcium-sensing receptor: a high-affinity presynaptic target for aminoglycoside-induced weakness. Neuropharmacology 57:502-5
Phillips, Cecilia G; Harnett, Mark T; Chen, Wenyan et al. (2008) Calcium-sensing receptor activation depresses synaptic transmission. J Neurosci 28:12062-70
Vyleta, Nicholas P; Smith, Stephen M (2008) Fast inhibition of glutamate-activated currents by caffeine. PLoS One 3:e3155
Smith, Stephen M; Renden, Robert; von Gersdorff, Henrique (2008) Synaptic vesicle endocytosis: fast and slow modes of membrane retrieval. Trends Neurosci 31:559-68
LeTourneau, Jennifer L; Hagg, Daniel S; Smith, Stephen M (2008) Baclofen and gamma-hydroxybutyrate withdrawal. Neurocrit Care 8:430-3
Chen, Wenyan; Harnett, Mark T; Smith, Stephen M (2007) Modulation of neuronal voltage-activated calcium and sodium channels by polyamines and pH. Channels (Austin) 1:281-90

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