Cholecystokinin facilitates glutamate release by increasing the number of readily releasable vesicles and releasing probability.
Cholecystokinin (CCK), a neuropeptide originally discovered in the gastrointestinal tract, is abundantly distributed in the mammalian brains including the hippocampus. Whereas CCK has been shown to increase glutamate concentration in the perfusate of hippocampal slices and in purified rat hippocampal synaptosomes, the cellular and molecular mechanisms whereby CCK modulates glutamatergic function remain unexplored. Here, we examined the effects of CCK on glutamatergic transmission in the hippocampus using whole-cell recordings from hippocampal slices. Application of CCK increased AMPA receptor-mediated EPSCs at perforant path-dentate gyrus granule cell, CA3-CA3 and Schaffer collateral-CA1 synapses without effects at mossy fiber-CA3 synapses. CCK-induced increases in AMPA EPSCs were mediated by CCK-2 receptors and were not modulated developmentally and transcriptionally. CCK reduced the coefficient of variation and paired-pulse ratio of AMPA EPSCs suggesting that CCK facilitates presynaptic glutamate release. CCK increased the release probability and the number of readily releasable vesicles with no effects on the rate of recovery from vesicle depletion. CCK-mediated increases in glutamate release required the functions of phospholipase C, intracellular Ca(2+) release and protein kinase Cgamma. CCK released endogenously from hippocampal interneurons facilitated glutamatergic transmission. Our results provide a cellular and molecular mechanism to explain the roles of CCK in the brain.
Deng
Pan-Yue
PY
Department of Pharmacology, School of Medicine and Health Sciences, University of North Dakota, Grand Forks, North Dakota 58203, USA.
Xiao
Zhaoyang
Z
Jha
Archana
A
Ramonet
David
D
Matsui
Toshimitsu
T
Leitges
Michael
M
Shin
Hee-Sup
HS
Porter
James E
JE
Geiger
Jonathan D
JD
Lei
Saobo
S
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002766:Cholecystokinin / Q000378:metabolism*; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D018698:Glutamic Acid / Q000378:metabolism*; D006624:Hippocampus / Q000254:growth & development / Q000502:physiology*; D066298:In Vitro Techniques; D042541:Intracellular Space / Q000502:physiology; D009474:Neurons / Q000502:physiology*; D015221:Potassium Channels / Q000378:metabolism; D017729:Presynaptic Terminals / Q000502:physiology; D011336:Probability; D011493:Protein Kinase C / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D043887:Receptor, Cholecystokinin B / Q000378:metabolism; D018091:Receptors, AMPA / Q000378:metabolism; D013569:Synapses / Q000502:physiology; D009435:Synaptic Transmission / Q000502:physiology*; D013572:Synaptic Vesicles / Q000502:physiology*; D010738:Type C Phospholipases / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
D015221:Potassium Channels; D043887:Receptor, Cholecystokinin B; D018091:Receptors, AMPA; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D002766:Cholecystokinin; C087857:protein kinase C gamma; D011493:Protein Kinase C; D010738:Type C Phospholipases; D002118:Calcium
Proc Natl Acad Sci U S A. 1996 Oct 15;93(21):11825-30
8876222
J Neurosci. 1999 Aug 15;19(16):7230-7
10436075
J Neurosci. 1984 Apr;4(4):1021-33
6325601
Brain Res. 2009 Jul 28;1282:10-9
19497313
Neuropeptides. 1988 Aug-Sep;12(2):95-103
2847075
Neuropharmacology. 1994 Jun;33(6):737-43
7936111
Curr Opin Pharmacol. 2006 Feb;6(1):24-9
16359919
Ann N Y Acad Sci. 1985;448:11-23
3896093
Regul Pept. 2000 Sep 25;93(1-3):79-83
11033055
Mol Endocrinol. 2002 Apr;16(4):847-58
11923480
Neuroscience. 1997 Jun;78(4):1005-16
9174069
J Neurophysiol. 2007 Jan;97(1):727-37
17135466
J Comp Neurol. 1981 Dec 10;203(3):335-50
7320233
World J Biol Psychiatry. 2006;7(4):231-7
17071543
J Neurosci. 1997 Jul 1;17(13):4994-5003
9185537
J Neurosci. 1984 Oct;4(10):2590-603
6149275
J Neurosci. 1987 Sep;7(9):2967-76
3625281
J Neurosci. 2001 Jun 1;21(11):3721-8
11356859
J Neurochem. 1994 Jan;62(1):76-85
7903356
Proc Natl Acad Sci U S A. 1989 Jul;86(13):5198-201
2740351
J Neurosci. 2000 Sep 15;20(18):6907-19
10995835
Am J Physiol. 1995 Nov;269(5 Pt 1):G628-46
7491953
J Neurochem. 1991 Oct;57(4):1398-404
1716664
Eur J Neurosci. 1998 Jun;10(6):2016-25
9753089
J Neurophysiol. 1995 Sep;74(3):990-1000
7500167
Neuron. 2002 Dec 19;36(6):1127-43
12495627
Science. 1996 Mar 1;271(5253):1294-7
8638114
Neuron. 2009 Jul 30;63(2):230-43
19640481
Neuropharmacology. 2008 Jan;54(1):117-28
17689570
J Med Chem. 1991 Apr;34(4):1505-8
2016728
Eur Neuropsychopharmacol. 2004 May;14(3):175-83
15056476
J Neurosci. 1990 Apr;10(4):1070-81
2329368
Ann N Y Acad Sci. 1999 Apr 30;868:233-85
10414301
Brain Res. 1988 Jun 7;451(1-2):309-18
3251590
Annu Rev Physiol. 2002;64:355-405
11826273
J Neurophysiol. 1993 Dec;70(6):2584-95
7509860
Neurosci Lett. 1988 Jul 19;90(1-2):51-6
3412648
Proc Natl Acad Sci U S A. 1994 Dec 20;91(26):12942-6
7809151
Biochem Biophys Res Commun. 2002 Apr 5;292(3):632-8
11922613
Biol Pharm Bull. 2007 Feb;30(2):297-302
17268069
Mol Pharmacol. 2007 Jul;72(1):208-18
17452494
J Comp Neurol. 1988 Oct 8;276(2):219-30
3220981
J Neurophysiol. 2003 May;89(5):2482-8
12611980
Ann N Y Acad Sci. 1985;448:361-74
2862830
Am J Physiol Cell Physiol. 2001 Jul;281(1):C17-23
11401823
Brain Res. 1987 Jul 7;415(1):197-203
3040174
J Neurosci. 2009 Jun 3;29(22):7349-58
19494156
Science. 1996 Aug 9;273(5276):788-91
8670417
Nat Neurosci. 2005 Oct;8(10):1319-28
16158066
Curr Med Chem. 1999 Jun;6(6):433-55
10213792
J Neurosci. 2001 Aug 15;21(16):5973-83
11487620
Eur J Pharmacol. 1996 Jun 27;307(2):125-32
8832213
J Pharmacol Exp Ther. 1994 May;269(2):725-31
7910212
J Physiol. 2006 Dec 1;577(Pt 2):497-511
16990402
Exp Neurol. 2001 Oct;171(2):210-8
11573973
J Biol Chem. 2009 Apr 17;284(16):10980-91
19244246
Nature. 1997 Sep 18;389(6648):290-3
9305844
Neurosci Lett. 1988 Dec 19;95(1-3):341-6
2852324
Neurosci Lett. 1997 Sep 26;234(1):67-70
9347948
J Comp Neurol. 1985 Jul 22;237(4):485-505
4044896
Brain Res. 1986 Jan 1;362(1):175-9
3002550
Peptides. 2001 Aug;22(8):1197-200
11457511
J Neurophysiol. 2007 Nov;98(5):2868-77
17804573
J Neurosci. 2006 May 10;26(19):5017-27
16687493
Brain Res. 1981 Feb 2;205(2):337-50
6162516
Neuron. 1999 Jun;23(2):399-409
10399944
Synapse. 1995 Oct;21(2):158-68
8584977
FEBS Lett. 1996 Feb 26;381(1-2):71-6
8641443
Nat Neurosci. 2007 Sep;10(9):1128-30
17676058
J Physiol. 2006 Apr 15;572(Pt 2):425-42
16455686