Several factors contribute to the degeneration and ultimately loss of neurons during aging and especially during Alzheimer's Disease (AD). One potentially critical factor is an increase in neuronal Ca2+ influx through L-type Ca2+ channels. The activity of L-type channels increases with age in rats, and an inhibitor of these channels impressively improves the learning capabilities of aged rabbits when given over several weeks. These findings suggest that L-type channels may be involved in aging-related neurological changes and the etiology of AD. Our objectives are to determine molecular changes of L-type channels that may contribute to the upregulation of L-type channel activity during aging. Based on our preliminary data, we hypothesize that: (A) an increase in protein kinase A (PKA)-mediated phosphorylation of L-type channels is responsible for their upregulation during aging; (B) beta-adrenergic receptors can control the elevation in phosphorylation of L-type channels by PKA. We will test these hypotheses by determining the phosphorylation status of L-type channels in brain samples from adult rats (some treated with beta-adrenergic agonists) and aging rats as a model for senile symptoms. Brain samples from adult and aging rats will be solubilized and L-type channels immunoprecipitated for further biochemical analysis of parameters that might change during aging, e.g., phosphorylation by PKA and other kinases. To test whether the number of L-type channels present in neurons is changed during aging, relative amounts of L-type channel proteins will be determined by immunoblotting and compared to the level of various pre- and postsynaptic marker proteins. PKA is associated with L-type channels. We will measure the relative amounts of PKA subunits and PKA anchoring proteins in the L-type channel immunocomplexes to test potential changes during aging that could explain the increase in PKA-mediated phosphorylation. Finally, we will investigate whether injection of the beta-adrenergic agonist isoproterenol upregulates PKA-mediated phosphorylation of L-type channels in adult rats.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG017502-03
Application #
6533839
Study Section
Special Emphasis Panel (ZRG1-BDCN-3 (01))
Program Officer
Wise, Bradley C
Project Start
2000-09-01
Project End
2005-08-31
Budget Start
2002-09-01
Budget End
2003-08-31
Support Year
3
Fiscal Year
2002
Total Cost
$357,460
Indirect Cost
Name
University of Iowa
Department
Pharmacology
Type
Schools of Medicine
DUNS #
041294109
City
Iowa City
State
IA
Country
United States
Zip Code
52242
Tseng, Pang-Yen; Henderson, Peter B; Hergarden, Anne C et al. (2017) ?-Actinin Promotes Surface Localization and Current Density of the Ca2+ Channel CaV1.2 by Binding to the IQ Region of the ?1 Subunit. Biochemistry 56:3669-3681
Turner, Matthew; Anderson, David E; Rajan, Sahana et al. (2016) Chemical shift assignments of the C-terminal EF-hand domain of ?-actinin-1. Biomol NMR Assign 10:219-22
Zhang, Yonghong; Matt, Lucas; Patriarchi, Tommaso et al. (2014) Capping of the N-terminus of PSD-95 by calmodulin triggers its postsynaptic release. EMBO J 33:1341-53
Speca, D J; Ogata, G; Mandikian, D et al. (2014) Deletion of the Kv2.1 delayed rectifier potassium channel leads to neuronal and behavioral hyperexcitability. Genes Brain Behav 13:394-408
Núñez-Santana, Félix Luis; Oh, Myongsoo Matthew; Antion, Marcia Diana et al. (2014) Surface L-type Ca2+ channel expression levels are increased in aged hippocampus. Aging Cell 13:111-20
Chen, Chao-Yin; Matt, Lucas; Hell, Johannes Wilhelm et al. (2014) Perampanel inhibition of AMPA receptor currents in cultured hippocampal neurons. PLoS One 9:e108021
Hell, Johannes W (2014) CaMKII: claiming center stage in postsynaptic function and organization. Neuron 81:249-65
Hall, Duane D; Dai, Shuiping; Tseng, Pang-Yen et al. (2013) Competition between ?-actinin and Ca²?-calmodulin controls surface retention of the L-type Ca²? channel Ca(V)1.2. Neuron 78:483-97
Zhang, Mingxu; Patriarchi, Tommaso; Stein, Ivar S et al. (2013) Adenylyl cyclase anchoring by a kinase anchor protein AKAP5 (AKAP79/150) is important for postsynaptic ?-adrenergic signaling. J Biol Chem 288:17918-31
Qian, Hai; Matt, Lucas; Zhang, Mingxu et al. (2012) ?2-Adrenergic receptor supports prolonged theta tetanus-induced LTP. J Neurophysiol 107:2703-12

Showing the most recent 10 out of 29 publications