title: Effects of essential amino acid deficiency: down-regulation of KCC2 and the GABAA receptor; disinhibition in the anterior piriform cortex.
abstract: The anterior piriform cortex (APC) is activated by, and is the brain area most sensitive to, essential (indispensable) amino acid (IAA) deficiency. The APC is required for the rapid (20 min) behavioral rejection of IAA deficient diets and increased foraging, both crucial adaptive functions supporting IAA homeostasis in omnivores. The biochemical mechanisms signaling IAA deficiency in the APC block initiation of translation in protein synthesis via uncharged tRNA and the general amino acid control kinase, general control nonderepressing kinase 2. Yet, how inhibition of protein synthesis activates the APC is unknown. The neuronal K(+) Cl(-) cotransporter, neural potassium chloride co-transporter (KCC2), and GABAA receptors are essential inhibitory elements in the APC with short plasmalemmal half-lives that maintain control in this highly excitable circuitry. After a single IAA deficient meal both proteins were reduced (vs. basal diet controls) in western blots of APC (but not neocortex or cerebellum) and in immunohistochemistry of APC. Furthermore, electrophysiological analyses support loss of inhibitory elements such as the GABAA receptor in this model. As the crucial inhibitory function of the GABAA receptor depends on KCC2 and the Cl(-) transmembrane gradient it establishes, these results suggest that loss of such inhibitory elements contributes to disinhibition of the APC in IAA deficiency. The circuitry of the anterior piriform cortex (APC) is finely balanced between excitatory (glutamate, +) and inhibitory (GABA, -) transmission. GABAA receptors use Cl(-), requiring the neural potassium chloride co-transporter (KCC2). Both are rapidly turning-over proteins, dependent on protein synthesis for repletion. In IAA (indispensable amino acid) deficiency, within 20 min, blockade of protein synthesis prevents restoration of these inhibitors; they are diminished; disinhibition ensues. GCN2 = general control non-derepressing kinase 2, eIF2α = α-subunit of the eukaryotic initiation factor 2.
authors.affiliation: Department of Anatomy, Physiology and Cell Biology, School of Veterinary Medicine, University of California, Davis, California, USA.
authors.forename: James W
authors.initials: JW
authors.lastname: Sharp
authors.forename: Catherine M
authors.initials: CM
authors.lastname: Ross-Inta
authors.forename: Irène
authors.initials: I
authors.lastname: Baccelli
authors.forename: John A
authors.initials: JA
authors.lastname: Payne
authors.forename: John B
authors.initials: JB
authors.lastname: Rudell
authors.forename: Dorothy W
authors.initials: DW
authors.lastname: Gietzen
mesh_terms: D000601:Amino Acids, Essential / Q000172:deficiency*; D000818:Animals; D015536:Down-Regulation; D019706:Excitatory Postsynaptic Potentials; D008297:Male; D009833:Olfactory Pathways / Q000378:metabolism*; D051381:Rats; D011963:Receptors, GABA-A / Q000096:biosynthesis*; D027981:Symporters / Q000096:biosynthesis*; D000096922:K Cl- Cotransporters
chemical_list: D000601:Amino Acids, Essential; D011963:Receptors, GABA-A; D027981:Symporters; D000096922:K Cl- Cotransporters
keywords: GCN2; chemosensor; eIF2α; indispensable amino acid; seizure; threonine
references.citation: Neuroscience. 2004;126(4):1053-62
references.pmid: 15207338
references.citation: J Nutr. 2003 Jul;133(7):2331-5
references.pmid: 12840202
references.citation: Am J Physiol. 1976 Oct;231(4):1263-6
references.pmid: 984211
references.citation: Biochem Soc Trans. 2006 Feb;34(Pt 1):7-11
references.pmid: 16246168
references.citation: Am J Physiol. 1996 Jul;271(1 Pt 2):R18-24
references.pmid: 8760199
references.citation: J Biol Chem. 1996 Jul 5;271(27):16245-52
references.pmid: 8663311
references.citation: Nutr Neurosci. 1998;1(5):373-81
references.pmid: 27406335
references.citation: J Neurosci. 2004 May 5;24(18):4478-88
references.pmid: 15128862
references.citation: Physiol Rev. 2011 Jul;91(3):1009-22
references.pmid: 21742794
references.citation: Science. 2005 Mar 18;307(5716):1776-8
references.pmid: 15774759
references.citation: Brain Res. 2002 Jan 4;924(1):1-9
references.pmid: 11743989
references.citation: Trends Neurosci. 2003 Apr;26(4):199-206
references.pmid: 12689771
references.citation: Proc Natl Acad Sci U S A. 2006 May 30;103(22):8465-8
references.pmid: 16709666
references.citation: Pflugers Arch. 1999 Aug;438(3):314-21
references.pmid: 10398861
references.citation: Annu Rev Nutr. 2007;27:63-78
references.pmid: 17328672
references.citation: Am J Physiol. 1971 Sep;221(3):929-35
references.pmid: 5570352
references.citation: Brain Res. 2000 Apr 7;861(1):77-87
references.pmid: 10751567
references.citation: J Neurosci. 2012 Aug 15;32(33):11356-64
references.pmid: 22895718
references.citation: J Nutr. 2001 Mar;131(3):851S-855S
references.pmid: 11238773
references.citation: Chem Senses. 2001 Jun;26(5):551-76
references.pmid: 11418502
references.citation: Br J Pharmacol. 2011 Nov;164 Suppl 1:S1-324
references.pmid: 22040146
references.citation: J Nutr. 1998 Apr;128(4):771-81
references.pmid: 9521642
references.citation: Neuron. 2011 Oct 6;72(1):49-56
references.pmid: 21982368
references.citation: Brain Res Mol Brain Res. 2002 Sep 30;105(1-2):11-8
references.pmid: 12399103
references.citation: Neurosci Biobehav Rev. 2002 Jun;26(4):393-428
references.pmid: 12204189
references.citation: J Comp Neurol. 2001 Jun 4;434(3):289-307
references.pmid: 11331530
references.citation: J Nutr. 2005 Jun;135(6 Suppl):1527S-30S
references.pmid: 15930464
references.citation: J Neurophysiol. 2003 Feb;89(2):1057-66
references.pmid: 12574480
references.citation: J Physiol. 2011 Mar 15;589(Pt 6):1317-47
references.pmid: 21224237
references.citation: Pflugers Arch. 2010 Oct;460(5):875-89
references.pmid: 20734201
references.citation: J Nutr. 2004 Apr;134(4):717-23
references.pmid: 15051816
references.citation: J Comp Neurol. 1978 Apr 15;178(4):711-40
references.pmid: 632378
references.citation: Science. 1957 Dec 27;126(3287):1343-4
references.pmid: 13495468
references.citation: Neuron. 2005 Dec 8;48(5):773-86
references.pmid: 16337915
references.citation: J Cell Biol. 2002 Dec 9;159(5):747-52
references.pmid: 12473684
references.citation: J Neurosci. 2004 May 12;24(19):4683-91
references.pmid: 15140939
references.citation: J Neurosci. 2002 Jun 1;22(11):4412-7
references.pmid: 12040048
references.citation: Exp Brain Res. 1990;82(2):451-5
references.pmid: 1981040
references.citation: J Neurosci. 2011 Feb 2;31(5):1583-90
references.pmid: 21289166
references.citation: Mol Neurobiol. 2012 Oct;46(2):332-48
references.pmid: 22674217
references.citation: J Comp Neurol. 1978 Oct 15;181(4):781-807
references.pmid: 690285
references.citation: J Cell Biol. 2001 May 28;153(5):1011-22
references.pmid: 11381086
references.citation: Neuron. 2011 Oct 6;72(1):41-8
references.pmid: 21982367
references.citation: Trends Neurosci. 2006 Aug;29(8):429-37
references.pmid: 16842864
references.citation: Trends Neurosci. 2006 Feb;29(2):91-9
references.pmid: 16406138
references.citation: Nature. 1999 Jan 21;397(6716):251-5
references.pmid: 9930699
references.citation: Neuropediatrics. 1999 Feb;30(1):1-4
references.pmid: 10222452
references.citation: J Nutr. 2004 Sep;134(9):2365-71
references.pmid: 15333730
references.citation: J Comp Neurol. 2006 Jan 20;494(3):485-94
references.pmid: 16320252
references.citation: Trends Pharmacol Sci. 2001 Mar;22(3):121-32
references.pmid: 11239575
references.citation: Nutr Neurosci. 2002 Apr;5(2):125-30
references.pmid: 12000082
references.citation: J Biol Chem. 1999 Apr 30;274(18):12656-64
references.pmid: 10212246