title: Kisspeptin inhibits a slow afterhyperpolarization current via protein kinase C and reduces spike frequency adaptation in GnRH neurons.
abstract: Kisspeptin signaling via its cognate receptor G protein-coupled receptor 54 (GPR54) in gonadotropin-releasing hormone (GnRH) neurons plays a critical role in regulating pituitary secretion of luteinizing hormone and thus reproductive function. GPR54 is G(q)-coupled to activation of phospholipase C and multiple second messenger signaling pathways. Previous studies have shown that kisspeptin potently depolarizes GnRH neurons through the activation of canonical transient receptor potential channels and inhibition of inwardly rectifying K(+) channels to generate sustained firing. Since the initial studies showing that kisspeptin has prolonged effects, the question has been why is there very little spike frequency adaption during sustained firing? Presently, we have discovered that kisspeptin reduces spike frequency adaptation and prolongs firing via the inhibition of a calcium-activated slow afterhyperpolarization current (I(sAHP)). GnRH neurons expressed two distinct I(sAHP), a kisspeptin-sensitive and an apamin-sensitive I(sAHP). Essentially, kisspeptin inhibited 50% of the I(sAHP) and apamin inhibited the other 50% of the current. Furthermore, the kisspeptin-mediated inhibition of I(sAHP) was abrogated by the protein kinase C (PKC) inhibitor calphostin C, and the PKC activator phorbol 12,13-dibutyrate mimicked and occluded any further effects of kisspeptin on I(sAHP). The protein kinase A (PKA) inhibitors H-89 and the Rp diastereomer of adenosine 3',5'-cyclic monophosphorothioate had no effect on the kisspeptin-mediated inhibition but were able to abrogate the inhibitory effects of forskolin on the I(sAHP), suggesting that PKA is not involved. Therefore, in addition to increasing the firing rate through an overt depolarization, kisspeptin can also facilitate sustained firing through inhibiting an apamin-insensitive I(sAHP) in GnRH neurons via a PKC.
authors.affiliation: Department of Physiology & Pharmacology, Oregon Health and Sciences University, Portland, OR 97239, USA.
authors.forename: Chunguang
authors.initials: C
authors.lastname: Zhang
authors.forename: Oline K
authors.initials: OK
authors.lastname: Rønnekleiv
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Kelly
mesh_terms: D000200:Action Potentials / Q000187:drug effects* / Q000502:physiology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D005260:Female; D007987:Gonadotropin-Releasing Hormone / Q000378:metabolism*; D059648:Kisspeptins / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D018408:Patch-Clamp Techniques; D011493:Protein Kinase C / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D059648:Kisspeptins; D007987:Gonadotropin-Releasing Hormone; D011493:Protein Kinase C; D002118:Calcium
keywords: apamin; calcium-activated potassium current; calcium-activated slow afterhyperpolarization current; gonadotropin-releasing hormone
references.citation: Endocrinology. 1979 May;104(5):1247-55
references.pmid: 571329
references.citation: J Neurosci. 2008 Apr 23;28(17):4423-34
references.pmid: 18434521
references.citation: Mol Cell Endocrinol. 2006 Jul 25;254-255:91-6
references.pmid: 16762492
references.citation: Endocrinology. 2006 Dec;147(12):5817-25
references.pmid: 16959837
references.citation: J Physiol. 2006 Jul 15;574(Pt 2):431-42
references.pmid: 16627563
references.citation: Neuroendocrinology. 2004;80(4):264-72
references.pmid: 15665556
references.citation: J Neurophysiol. 1995 Dec;74(6):2749-53
references.pmid: 8747230
references.citation: Endocrinology. 2007 May;148(5):2383-90
references.pmid: 17289846
references.citation: Endocrinology. 2008 Sep;149(9):4605-14
references.pmid: 18483150
references.citation: Science. 1983 Sep 9;221(4615):1050-2
references.pmid: 6879204
references.citation: Proc Natl Acad Sci U S A. 2005 Feb 1;102(5):1761-6
references.pmid: 15665093
references.citation: J Neurosci. 2009 Apr 29;29(17):5616-27
references.pmid: 19403828
references.citation: J Biol Chem. 2001 Sep 14;276(37):34631-6
references.pmid: 11457843
references.citation: J Neurophysiol. 2000 Apr;83(4):2071-9
references.pmid: 10758117
references.citation: Science. 1988 Jul 29;241(4865):545-51
references.pmid: 2456612
references.citation: Prog Neurobiol. 2002 Apr;66(5):345-53
references.pmid: 12015199
references.citation: Proc Natl Acad Sci U S A. 1995 Dec 5;92(25):11716-20
references.pmid: 8524835
references.citation: J Neurosci. 2004 Sep 1;24(35):7718-26
references.pmid: 15342739
references.citation: Neuroendocrinology. 2006;83(5-6):275-81
references.pmid: 16940711
references.citation: J Neurosci. 2005 Dec 7;25(49):11349-56
references.pmid: 16339030
references.citation: J Neurophysiol. 2010 Oct;104(4):2052-62
references.pmid: 20719929
references.citation: Endocrinology. 2008 Jul;149(7):3598-604
references.pmid: 18372332
references.citation: Eur J Neurosci. 2003 Dec;18(12):3155-66
references.pmid: 14686890
references.citation: Neuron. 2002 Mar 28;34(1):107-14
references.pmid: 11931745
references.citation: Ann N Y Acad Sci. 1999 Apr 30;868:370-8
references.pmid: 10414306
references.citation: Rev Endocr Metab Disord. 2006 Dec;7(4):257-63
references.pmid: 17206526
references.citation: J Physiol. 1979 May;290(2):433-40
references.pmid: 469785
references.citation: Endocrinology. 2004 Sep;145(9):4073-7
references.pmid: 15217982
references.citation: Proc Natl Acad Sci U S A. 2007 Jun 19;104(25):10714-9
references.pmid: 17563351
references.citation: Endocrinology. 2007 Oct;148(10):4927-36
references.pmid: 17595229
references.citation: Endocrinology. 2000 Jan;141(1):412-9
references.pmid: 10614664
references.citation: J Neurosci. 2007 Sep 19;27(38):10153-64
references.pmid: 17881521
references.citation: J Exp Biol. 1988 Sep;139:51-65
references.pmid: 2850339
references.citation: Mol Pharmacol. 2006 Nov;70(5):1494-502
references.pmid: 16877678
references.citation: Endocrinology. 2008 Apr;149(4):1979-86
references.pmid: 18162521
references.citation: Mol Cell Endocrinol. 2013 Mar 10;367(1-2):85-97
references.pmid: 23305677
references.citation: J Neurosci. 2009 Mar 25;29(12):3920-9
references.pmid: 19321788
references.citation: Brain Res. 2010 Dec 10;1364:10-24
references.pmid: 20920482
references.citation: J Neurosci. 2002 Mar 1;22(5):1618-28
references.pmid: 11880492
references.citation: Trends Neurosci. 1996 Apr;19(4):150-4
references.pmid: 8658599
references.citation: J Physiol. 2007 Mar 1;579(Pt 2):363-73
references.pmid: 17158174
references.citation: Pflugers Arch. 2005 May;450(2):96-110
references.pmid: 15654629
references.citation: Eur J Endocrinol. 2006 Nov;155 Suppl 1:S11-6
references.pmid: 17074983
references.citation: Endocrinology. 2009 Mar;150(3):1400-12
references.pmid: 18948403
references.citation: J Neurosci. 2010 May 5;30(18):6214-24
references.pmid: 20445047
references.citation: Endocrinology. 2011 Jun;152(6):2387-99
references.pmid: 21486932
references.citation: Mol Pharmacol. 2010 Dec;78(6):1088-95
references.pmid: 20843955
references.citation: J Neurosci. 2008 Mar 19;28(12):3209-20
references.pmid: 18354024
references.citation: Endocrinology. 2005 Oct;146(10):4431-6
references.pmid: 15976058
references.citation: Annu Rev Physiol. 2012;74:245-69
references.pmid: 21942705
references.citation: Front Neuroendocrinol. 2010 Jul;31(3):259-69
references.pmid: 20594958
references.citation: Nat Neurosci. 2005 Feb;8(2):173-8
references.pmid: 15643430
references.citation: Neuron. 1993 Dec;11(6):1023-35
references.pmid: 8274274
references.citation: Neuroendocrinology. 2011;93(2):114-20
references.pmid: 21051881
references.citation: J Neurophysiol. 2010 Sep;104(3):1758-67
references.pmid: 20660425
references.citation: J Physiol. 1984 Sep;354:319-31
references.pmid: 6434729
references.citation: Endocrinology. 2008 May;149(5):2459-66
references.pmid: 18218690
references.citation: Endocrinology. 2009 May;150(5):2388-94
references.pmid: 19164470
references.citation: Endocrinology. 2002 Mar;143(3):1097-107
references.pmid: 11861537