In addition to their bioenergetic function, mitochondria are critical regulators of Ca signaling in neurons. Mitochondria efficiently buffer Ca2+ influx during excitation and limit the amplitude of the cytosolic Ca2+ concentration ([Ca2+]i) increase. Rapid Ca2+ uptake is followed by a slower Ca release from mitochondria, completing stimulus-induced mitochondrial Ca2+ cycle. By shaping [Ca2+]i response, mitochondria can modulate numerous Ca2+-dependent neuronal functions. At the same time, impairment of mitochondrial Ca2+ transport is the key factor leading to neuronal damage in stroke and in a number of neurodegenerative disorders. Despite significant progress, many questions remain about the spatiotemporal organization, function and modulation of mitochondrial Ca2+ cycling in neurons and, specifically, about the mechanisms regulating the transition from physiology to pathophysiology. Our overall hypothesis is that mitochondrial Ca2+ cycling controls diverse neuronal functions and that the decision between physiological and pathological outcomes is influenced by reversible phosphorylation of mitochondrial proteins. We will initially focus on two physiological processes, transmitter release (Aim 1) and activation of transcription (Aim 2), by studying spatiotemporal organization and the role of mitochondrial Ca2+ transport in two morphologically and functionally distinct cellular compartments, presynaptic boutons and the cell soma, respectively. We will then investigate how protein kinase A and protein phosphatase 2A modulate mitochondrial Ca2+ signaling and Ca2+-dependent processes, such as neurotransmission, transcription activation and excitotoxicity (Aim 3). Both enzymes are targeted to the outer mitochondrial membrane (OMM), but exhibit opposite effects on cell survival, and are predicted to differentially influence mitochondria-dependent functions. The proposed studies will advance our understanding of how mitochondrial Ca2+ transporters interplay with protein kinases and phosphatases in neurons to trigger a specific physiological or pathological response.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS054614-05
Application #
7878689
Study Section
Neurotransporters, Receptors, and Calcium Signaling Study Section (NTRC)
Program Officer
Stewart, Randall R
Project Start
2006-07-15
Project End
2012-06-30
Budget Start
2010-07-01
Budget End
2012-06-30
Support Year
5
Fiscal Year
2010
Total Cost
$287,126
Indirect Cost
Name
University of Iowa
Department
Pharmacology
Type
Schools of Medicine
DUNS #
062761671
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Loo, Lipin; Shepherd, Andrew J; Mickle, Aaron D et al. (2012) The C-type natriuretic peptide induces thermal hyperalgesia through a noncanonical G??-dependent modulation of TRPV1 channel. J Neurosci 32:11942-55
Ulrich, Jason D; Kim, Man-Su; Houlihan, Patrick R et al. (2012) Distinct activation properties of the nuclear factor of activated T-cells (NFAT) isoforms NFATc3 and NFATc4 in neurons. J Biol Chem 287:37594-609
Merrill, Ronald A; Dagda, Ruben K; Dickey, Audrey S et al. (2011) Mechanism of neuroprotective mitochondrial remodeling by PKA/AKAP1. PLoS Biol 9:e1000612
Jang, Jun Ho; Clark, J David; Li, Xiangqi et al. (2010) Nociceptive sensitization by complement C5a and C3a in mouse. Pain 148:343-52
Jenkins, Meagan A; Christel, Carl J; Jiao, Yuxia et al. (2010) Ca2+-dependent facilitation of Cav1.3 Ca2+ channels by densin and Ca2+/calmodulin-dependent protein kinase II. J Neurosci 30:5125-35
Kim, Man-Su; Usachev, Yuriy M (2009) Mitochondrial Ca2+ cycling facilitates activation of the transcription factor NFAT in sensory neurons. J Neurosci 29:12101-14
Medvedeva, Y V; Kim, M-S; Schnizler, K et al. (2009) Functional tetrodotoxin-resistant Na(+) channels are expressed presynaptically in rat dorsal root ganglia neurons. Neuroscience 159:559-69
Lu, Yuan; Zhang, Mingxu; Lim, Indra A et al. (2008) AKAP150-anchored PKA activity is important for LTD during its induction phase. J Physiol 586:4155-64
Schnizler, Katrin; Shutov, Leonid P; Van Kanegan, Michael J et al. (2008) Protein kinase A anchoring via AKAP150 is essential for TRPV1 modulation by forskolin and prostaglandin E2 in mouse sensory neurons. J Neurosci 28:4904-17
Dagda, Ruben K; Merrill, Ronald A; Cribbs, J Thomas et al. (2008) The spinocerebellar ataxia 12 gene product and protein phosphatase 2A regulatory subunit Bbeta2 antagonizes neuronal survival by promoting mitochondrial fission. J Biol Chem 283:36241-8

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