Insulin-stimulated translocation of GLUT4 to the plasma membrane in rat hippocampus is PI3-kinase dependent.
In the central nervous system (CNS) insulin mediates a variety of effects including feeding, metabolism and cognition. The cognitive enhancing effects of insulin are proposed to be mediated through activation of insulin receptors in the hippocampus, an important integration center for learning and memory in the mammalian brain. Since less is known regarding insulin signaling events in the hippocampus, the aim of the current study was to determine whether insulin stimulates similar signaling cascades and GLUT4 translocation in the rat hippocampus as has been described in peripheral tissues. Intracerebroventricular administration of insulin increases hippocampal insulin levels and also stimulates the phosphorylation of Akt in a time-dependent manner. Insulin also stimulates the translocation of GLUT4 to hippocampal plasma membranes in a time course that mirrors the increases in glucose uptake observed during the performance of hippocampal-dependent tasks. Insulin stimulated phosphorylation of Akt and translocation of GLUT4 were blocked by pretreatment with the PI3-kinase inhibitor LY294002. Confocal immunofluorescence determined that insulin stimulated phosphorylation of Akt was localized to neurons and colocalized with the insulin receptor and GLUT4 in the rat hippocampus, thereby identifying the functional anatomical substrates of insulin signaling in the hippocampus. These results demonstrate that insulin-stimulated translocation of GLUT4 to the plasma membrane in the rat hippocampus occurs via similar mechanisms as described in peripheral tissues and suggests that insulin-mediated translocation of GLUT4 may provide a mechanism through which hippocampal neurons rapidly increase glucose utilization during increases in neuronal activity associated with hippocampal-dependent learning.
Grillo
C A
CA
Department of Pharmacology, Physiology and Neuroscience, University of South Carolina School of Medicine, 6439 Garner's Ferry Road, Columbia, SC 29208, USA.
Piroli
G G
GG
Hendry
R M
RM
Reagan
L P
LP
D000818:Animals; D002462:Cell Membrane / Q000187:drug effects / Q000502:physiology*; D002867:Chromones / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005455:Fluorescent Antibody Technique; D051275:Glucose Transporter Type 4 / Q000378:metabolism*; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology*; D007328:Insulin / Q000378:metabolism*; D008297:Male; D018613:Microscopy, Confocal; D009025:Morpholines / Q000494:pharmacology; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D021381:Protein Transport / Q000187:drug effects / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011972:Receptor, Insulin / Q000378:metabolism; D013997:Time Factors
D002867:Chromones; D004791:Enzyme Inhibitors; D051275:Glucose Transporter Type 4; D007328:Insulin; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011972:Receptor, Insulin; C495694:Slc2a4 protein, rat; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
Neuroscience. 1997 Oct;80(4):1033-40
9284058
Eur J Neurosci. 2008 Aug;28(3):588-98
18702730
Diabetes. 1992 May;41(5):557-70
1568525
Brain Res. 1994 Oct 3;659(1-2):292-7
7820678
Neurology. 2008 Feb 5;70(6):440-8
17942819
Endocrinology. 2006 May;147(5):2550-6
16497805
J Biol Chem. 1999 Jan 29;274(5):2593-6
9915783
Trends Neurosci. 2000 Nov;23(11):542-9
11074263
Proc Natl Acad Sci U S A. 2001 Feb 27;98(5):2820-5
11226324
Eur J Pharmacol. 2004 Apr 19;490(1-3):71-81
15094074
Cell. 1989 Apr 21;57(2):305-15
2649253
Behav Neurosci. 2005 Oct;119(5):1389-95
16300445
J Biol Chem. 1999 Dec 3;274(49):34893-902
10574963
Int Rev Neurobiol. 2002;51:289-324
12420363
Proc Natl Acad Sci U S A. 1989 Apr;86(8):2535-9
2649883
J Comp Neurol. 2002 Oct 14;452(2):103-14
12271485
Anal Biochem. 1976 May 7;72:248-54
942051
Curr Opin Pharmacol. 2007 Dec;7(6):633-7
18023616
Neuroendocrinology. 2007;85(2):71-80
17426391
Behav Cogn Neurosci Rev. 2002 Dec;1(4):264-80
17712984
Neurosci Lett. 2001 Sep 14;310(2-3):101-4
11585577
Neuroendocrinology. 2001 Oct;74(4):270-80
11598383
Proc Natl Acad Sci U S A. 1993 Sep 1;90(17):7956-60
8367447
Trends Cell Biol. 2002 Feb;12(2):65-71
11849969
J Comp Neurol. 1993 Jul 15;333(3):375-97
8349849
Brain Res. 2000 Apr 17;862(1-2):292-300
10799703
Physiol Behav. 2000 Feb;68(4):509-14
10713291
Proc Natl Acad Sci U S A. 2000 Mar 14;97(6):2881-5
10706633
Brain Res. 1998 Jun 22;797(1):1-11
9630471
Curr Opin Neurobiol. 1995 Apr;5(2):205-16
7620309
J Neurosci. 2009 Apr 22;29(16):5193-201
19386915
Endocr Rev. 1995 Feb;16(1):3-34
7758431
Endocrinology. 1990 Dec;127(6):3234-6
2249648
Eur J Pharmacol. 2004 Apr 19;490(1-3):13-24
15094070
Psychoneuroendocrinology. 2004 Nov;29(10):1326-34
15288712
Arch Gen Psychiatry. 1999 Dec;56(12):1135-40
10591291