1. The_Skeptic

    The_Skeptic Junior Member

    I just came across an article online that was published last year about a protein called kisspeptin that is key in triggering puberty and sexual maturation in teens.
    It seems to directly stimulate GnRH.

    The first link is the article. The second two links are medical abstracts.


    http://www.gestion.uco.es/gestion/comunica/dossier/mostrar/prensa/dossier/20050722/13.pdf
    Kisspeptin directly stimulates gonadotropin-releasing hormone release via G protein-coupled receptor 54
    Kisspeptin-10 stimulates the hypothalamic-pituitary-gonadal axis in adult male rats following central and peripheral administration
     
    Last edited by a moderator: Mar 2, 2012
  2. The_Skeptic

    The_Skeptic Junior Member

    Does anyone have any comments about this article? I find it pretty interesting.
     
  3. Axl

    Axl Junior Member

    I have read the article. Interesting: great link!

    I have never heard of it. I hope somebody can comment on these articles...
     
  4. The_Skeptic

    The_Skeptic Junior Member

    NeuroSearch sees kisspeptin as libido stimulator, treatment of abnormal puberty

    COPENHAGEN (AFX) - NeuroSearch AS said it sees the hormone-like peptide kisspeptin as a libido stimulator and a treatment of abnormal puberty or growth.

    The Danish healthcare company said its scientists, working in collaboration with scientists at Centre Nationale de la Recherche Scientifique (CNRS) in Strasbourg, have shown that kisspeptin plays a central role in controlling libido.

    The peptide fully re-established the sexual function of hamsters, which are sexually active only during the summer period, while they were kept under winter-like conditions, NeuroSearch said.

    'These are important findings which demonstrate that sexual behaviour is controlled by the brain and that cells containing kisspeptin fully or partly regulate libido,' it said.

    Kisspeptin, which was discovered in 2003, has so far been considered only to influence the development of puberty.

    NeuroSearch said the latest research findings leave new opportunities for the treatment of low or no libido as well as for the treatment of abnormal puberty or growth.

    The kisspeptin project originates from the company's early drug discovery within target identification. The continued drug discovery activities in the project will focus on the identification of kisspeptin modulators as the basis for novel drug candidates, it said.

    http://www.forbes.com/markets/feeds/afx/2006/12/07/afx3236215.html
     
  5. KidCapriB

    KidCapriB Junior Member

    Kisspeptin Directly Causes GnRH Production at Hypothalamus

    this is a recent discovery by scientists. a hormone called Kisspeptin directly binds to receptors on the hypothalamus and stimulates the production of GnRH, which we all know in turn stimulates the pituitary to produce LH and FSH (which is responsible for testosterone production). This seems like a very safe way of HRT or possibly jumpstart your HPTA, you're starting from the source...the hypothalamus. Apparently kisspeptin is the reason why people go into puberty.

    link 1: http://www.pnas.org/cgi/content/full/102/5/1761?ck=nck

    and for a more straightforward definition look at wikipedia, type in kisspeptin
     
  6. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Future pct?

    Kisspeptin May Normalize Reproductive Hormones In Women With Hypothalamic Amenorrhea.

    MedPage Today (3/18, Gever - Medical News: BES: Peptide Normalizes Hormones in Infertile Women - in Meeting Coverage, BES from MedPage Today) reported that, according to poster presentation at an endocrinology meeting, "injections of a natural human peptide hormone called kisspeptin restored reproductive hormones to potentially functional levels in women with hypothalamic amenorrhea." In a study of "20 patients with hypothalamic amenorrhea, followed by a placebo-controlled trial in 10 patients," researchers found that women went "from near-zero levels of luteinizing hormone (LH) and follicle-stimulating hormone (FSH)" to "LH levels of about 10 IU/L and FSH at about 2.5 IU/L after eight weeks."
     
  7. Kwirion

    Kwirion Member

    Re: Future pct?

    Kisspeptin-54 Stimulates the Hypothalamic-Pituitary Gonadal Axis in Human Males
    Kisspeptin-54 Stimulates the Hypothalamic-Pituitary Gonadal Axis in Human Males -- Dhillo et al. 90 (12): 6609 -- Journal of Clinical Endocrinology & Metabolism

     
  8. Kwirion

    Kwirion Member

    Re: Future pct?

    Found in Web...

     
  9. clintchiz2000

    clintchiz2000 Junior Member

    Re: Future pct?

    Correct me if I'm wrong, but is article 1 article saying that it stimulates the testes and raises LH and FSH while the other says it causes testicular degeneration?
     
  10. Kwirion

    Kwirion Member

    Re: Future pct?

    Posibly dosage dependent.

    Mixed results suggest that we need further research.
     
  11. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Kisspeptins And The Control Of Gonadotrophin Secretion

    The seminal discovery of gonadotropin-releasing hormone (GnRH) and subsequent studies have categorically established its role as the final neuroendocrine conduit for control of the gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) by diverse central nervous system inputs. LH and FSH act in concert to stimulate sex steroid secretion and gametogenesis in the testes and ovaries. Appropriate gonadotropin pulse frequency and amplitude is crucial for normal reproduction and disruption is associated with pathological conditions such as hypothalamic amenorrhea (low pulse frequency) and polycystic ovarian syndrome (high pulse frequency). However, the precise mechanisms whereby inputs such as metabolic status and sex steroids regulate GnRH secretion remained cryptic as GnRH neurons lack requisite receptors, estrogen receptor alpha and leptin.

    Recent discoveries of naturally occurring mutations have revolutionized our understanding of the neuroendocrine regulation of gonadotropins. The discovery that mutations in the human and rodent G-protein-coupled receptor 54 (GPR54 also referred to as KISS1R) resulted in failure to progress through puberty and achieve adult reproductive function led to the recognition that GPR54 and its cognate ligands, kisspeptins, are required for GnRH release and downstream gonadotropin secretion. The localization of kisspeptins to arcuate nucleus (ARC) neurons, and its potential involvement as a component of the GnRH pulse generator suggested a role for kisspeptin in the regulation of GnRH pulse frequency. This postulate is supported by a slowing of LH pulse frequency after kisspeptin antagonist injection into the ARC of rats and an increase in LH pulse frequency after kisspeptin administration in men. Kisspeptin neurons express receptors for sex steroids which modulate kisspeptin gene expression, thereby providing a relay for steroid hormone feedback on GnRH neuron regulation.

    Kisspeptin neurons in the ARC have been shown to also express neurokinin B (NKB) and dynorphin A (DYN) peptides and are therefore called KNDY neurons. Inactivating mutations in the genes encoding NKB (TAC3) and its cognate receptor, NK3R (TACR3), have also been recently shown, like GPR54 mutations, to result in hypogonadotropic hypogonadism; characterized by a failure to progress through puberty . In contrast, TACR3-inactivating mutation in mice does not result in a phenotype of reproductive deficiency.

    In order to contribute to an understanding of the hierarchy of roles of kisspeptin and NKB in the neuroendocrine control of GnRH pulsatility, researchers have administered kisspeptin to patients with hypogonadotropic hypogonadism resulting from naturally occurring loss-of-function mutations in the NKB ligand and its receptor. These patients are characterized by very low LH but normal or near-normal FSH circulating concentrations, consistent with low GnRH pulse frequency. In contrast, inactivating mutations in the kisspeptin receptor result in low circulating concentrations of both LH and FSH. Since GnRH neurons express the GPR54 receptor but apparently not NK3R in sheep and mice and kisspeptin (KNDY) neurons express NK3R, they hypothesized that NKB secreted from KNDY neurons acts in an autocrine or paracrine manner to enhance kisspeptin secretion, and that kisspeptin alone is sufficient to elicit GnRH pulsatility. To test this postulate, they infused kisspeptin at a GPR54- saturating concentration in patients with TAC3- and TACR3-inactivating mutations and demonstrated a restoration of LH pulsatility. This is the first indication of cooperative interactions of neuropeptides within a single neuronal population eliciting a pulsatile output essential for human health, and provides information on the hierarchy of kisspeptin and NKB in regulating GnRH secretion in humans.

    [​IMG]
    Schematic of proposed actions of a KNDY neuron on GnRH secretion summarizing findings from human and animal studies. Impacts of NKB and kisspeptin release on GnRH neuron secretion and LH and FSH responses in normal subjects (left) and patients with NKB- and NK3R-inactivating mutations (right). In normal subjects NKB acts in an autocrine (shown) or possibly paracrine (not shown) modality to reinforce kisspeptin secretion, which stimulates the GnRH neuron to secrete GnRH in pulses with a frequency interval of about 90 min. This results in corresponding LH pulses and normal FSH levels. In patients with NKB-inactivating (TAC3) and NK3R-inactivating (TACR3) mutations the absence of NKB stimulation of the KNDY neuron results in low kisspeptin secretion and resulting low GnRH pulse frequency with correspondingly low LH pulse frequency and amplitude, and lower end of normal FSH secretion. Continuous infusion of kisspeptin overrides this deficiency to restore the normal pattern of LH pulses and a small increase in FSH. Note that the most parsimonious scheme involving kisspeptin and NKB is presented. In reality a greater complexity of regulation of the KNDY neuron including DYN and other regulators, as well as additional inputs into the GnRH neuron will be operative.


    Young J, George JT, Tello JA, et al. Kisspeptin Restores Pulsatile LH Secretion in Patients with Neurokinin B Signaling Deficiencies: Physiological, Pathophysiological and Therapeutic Implications. Neuroendocrinology. Kisspeptin Restores Pulsatile LH Secretion in Patients with Neurokinin B Signaling Deficiencies: Physiological, Pathophysiological and Therapeutic Implications

    Pulsatile gonadotropin-releasing hormone (GnRH) is crucial to normal reproductive function and abnormalities in pulse frequency give rise to reproductive dysfunction. Kisspeptin and neurokinin B (NKB), neuropeptides secreted by the same neuronal population in the ventral hypothalamus, have emerged recently as critical central regulators of GnRH and thus gonadotropin secretion. Patients with mutations resulting in loss of signaling by either of these neuroendocrine peptides fail to advance through puberty but the mechanisms mediating this remain unresolved. We report here that continuous kisspeptin infusion restores gonadotropin pulsatility in patients with loss-of-function mutations in NKB (TAC3) or its receptor (TAC3R), indicating that kisspeptin on its own is sufficient to stimulate pulsatile GnRH secretion. Moreover, our findings suggest that NKB action is proximal to kisspeptin in the reproductive neuroendocrine cascade regulating GnRH secretion, and may act as an autocrine modulator of kisspeptin secretion. The ability of continuous kisspeptin infusion to induce pulsatile gonadotropin secretion further indicates that GnRH neurons are able to set up pulsatile secretion in the absence of pulsatile exogenous kisspeptin.


    Dedes I. Kisspeptins and the control of gonadotrophin secretion. Syst Biol Reprod Med. Kisspeptins and the control of gonadotrophin secretion, Systems Biology in Reproductive Medicine, Informa Healthcare

    Kisspeptins, the peptide products of the KiSS-1 gene, bind to the G protein coupled receptor 54 (GPR54). Since 2003, research has revealed the important role of kisspeptins in initiating puberty, timing puberty and regulating fertility in adulthood. Specific mutations in GPR54 gene cause either delayed/absent puberty or precocious puberty. The KiSS-1/GPR54 system stimulates the gonadotrophin releasing hormone (GnRH) neurons and is involved in the feedback regulation of the HPG axis by gonadal steroids. Different hypothalamic nuclei are involved in negative (arcuate nucleus; ARC) and positive (anteroventral periventricular nucleus; AVPV) feedback in mice. Continuous administration of kisspeptins down-regulates the HPG axis. During pregnancy, kisspeptins are secreted from the placenta in large amounts and are responsible for the physiological invasion of primary human trophoblast. Kisspeptins have been administered to normal male and female individuals as well as to women with hypothalamic secondary amenorrhoea. In all cases, gonadotrophin secretion was potently stimulated. Kisspeptin antagonists have been synthesized to successfully suppress GnRH and gonadotrophin release. These agonists and antagonists appear as valuable new tools for manipulating the HPG axis and are promising drugs for future treatment. The scope of this review highlights the role of kisspeptins in regulating gonadotrophin secretion and explores their possible therapeutic use.
     

    Attached Files:

  12. zkt

    zkt Member

    Anyone for theorizing that, perhaps, hcg mimics Kiss in some fashion?
     
  13. zkt

    zkt Member

    Last edited: Mar 2, 2012
  14. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    George JT, Veldhuis JD, Tena-Sempere M, Millar RP, Anderson RA. Exploring the pathophysiology of hypogonadism in men with type 2 diabetes: Kisspeptin-10 stimulates serum testosterone and LH secretion in men with type 2 diabetes and mild biochemical hypogonadism. Clin Endocrinol (Oxf). Exploring the pathophysiology of hypogonadism in men with type 2 diabetes: Kisspeptin-10 stimulates serum testosterone and LH secretion in men with type 2 diabetes and mild biochemical hypogonadism - George - Clinical Endocrinology - Wiley Online Lib

    RATIONALE: Low serum testosterone is commonly observed in men with type 2 diabetes (T2DM) but the neuroendocrine pathophysiology remains to be elucidated.

    OBJECTIVES: The hypothalamic neuropeptide kisspeptin integrates metabolic signals with the reproductive axis in animal models. We hypothesised that administration of exogenous kisspeptin-10 will restore luteinising hormone (LH) and testosterone secretion in hypotestosteronaemic men with T2DM.

    PARTICIPANTS: Five hypotestosteronaemic men with T2DM (age 33.6+/-3 years, BMI 40.6+/-6.3, total testosterone 8.5+/-1.0 nmol/L, LH 4.7+/-0.7 IU/L, HbA(1c) 7.4+/-2 %, duration of diabetes <5 years) and seven age-matched healthy men. Experiment 1: Mean LH increased in response to intravenous administration of kisspeptin-10 (0.3 mcg/kg bolus) in both healthy men (5.5+/-0.8 to 13.9+/-1.7 IU/L P <0.001) and in T2DM (4.7+/-0.7 to 10.7+/-1.2 IU/L P=0.02) with comparable DeltaLH (P=0.18). Experiment 2: Baseline 10-min serum sampling for LH and hourly testosterone measurements were performed in four T2DM men over 12 hours. An intravenous infusion of kisspeptin-10 (4 mcg/kg/hr) was administered for 11 hours, 5 days later. There were increases in LH (3.9+/-0.1 IU/L to 20.7+/-1.1 IU/L P=0.03) and testosterone (8.5+/-1.0 to 11.4+/-0.9 nmol/L, P=0.002). LH pulse frequency increased from 0.6+/-0.1 to 0.9+/-0 pulses/hr (P=0.05) and pulsatile component of LH secretion from 32.1+/-8.0 IU/L to 140.2+/-23.0 IU/L (P=0.007).

    CONCLUSIONS: Kisspeptin-10 administration increased LH pulse frequency and LH secretion in hypotestosteronaemic men with T2DM in this proof-of-concept study, with associated increases in serum testosterone. These data suggest a potential novel therapeutic role for kisspeptin agonists in enhancing endogenous testosterone secretion in men with T2DM and central hypogonadism.
     
  15. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Kaur K, Allahbadia G, Singh M. Kisspeptins in human reproduction - future therapeutic potential. Journal of Assisted Reproduction and Genetics 2012;29(10):999-1011. Kisspeptins in human reproduction—future therapeutic potential - Springer

    Objective - Kisspeptins (Kps), were first found to regulate the hypothalamopituitary-gonadal axis (HPG) axis in 2003, when two groups-demonstrated that mutations of GPR54 causes idiopathic hypogonadotropic hypogonadism (IHH) characterized by delayed puberty. Objective of this review is to highlight both animal and human discoveries in KISS1/GPR54 system in last decade and extrapolate the therapeutic potential in humans from till date human studies.

    Design - A systematic review of international scientific literature by a search of PUBMED and the authors files was done for Kp in reproduction, metabolic control & signal transduction.

    Setting - None

    Patient(s): In human studies—normal subjects patients with HH, or HA.

    Main outcome measures: - Effects of Kp on puberty, brain sexual maturation, regulation of GnRH secretion, metabolic control of GnRH Neurons (N).

    Results - Kps/GPR54 are critical for brain sexual maturation, puberty and regulation of reproduction. Kps have been implicated in mediating signals to GnRH N—positive and negative feedback, metabolic input. Ability of Kp neurons to coordinate signals impinging on the HPG axis makes it one of most important regulators of reproductive axis since GnRH N’s lack many receptors, with Kp neurons serving as upstream modulators.

    Conclusions - Kps have proven as pivotal regulators of the reproduction, with the ability to integrate signals from both internal and external sources. Knowledge about signaling mechanisms involved in Kp stimulation of GnRH and with human studies has made it possible that therapeutically available Kp agonists/antagonists may be used for treatment of delayed puberty/HH, Hypothalamic amenorrhea and in prevention of spread of malignant ovarian/gonadal malignancies along with uses in some eating disorders.

    Normal physiology and the pathophysiological process underpinning of Kiss1 neuron involvement in obesity hypothesis

    [​IMG]
     

    Attached Files:

  16. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Mammalian Hypothalamic Pituitary Gonadal Axis

    Pulsatile secretion of gonadotrophic releasing hormone (GnRH) stimulates the anterior pituitary to release the gonadotrophic hormones, luteinizing hormone (LH), and follicle-stimulating hormone (FSH). These act on the gonads to promote gamete formation and the production of gonadal steroid hormones, which form feedback loops to regulate GnRH, LH, and FSH release.

    Kisspeptin (Kiss1) neurons act as a principal relay for steroid feedback on GnRH secretion. In females, high levels of estrogens and progesterone stimulate kisspeptin neurons of the AVPV to induce the preovulatory surge of GnRH/LH, whereas they inhibit KISS1 expression in the arcuate nucleus (ARC). In the male, GnRH and gonadotrophic hormone release are negatively regulated by circulating testosterone, partly through the activity of kisspeptin neurons of the ARC.

    POA, preoptic area; AVPV, anteroventral periventricular nucleus; ME, median eminence.

    [​IMG]
     

    Attached Files:

  17. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Simonneaux V, Ancel C, Gauer F, Poirel V-J. Kisspeptins and RFRP-3 act in concert to synchronize rodent reproduction with seasons. Frontiers in Neuroscience 2013;7. Frontiers | Kisspeptins and RFRP-3 Act in Concert to Synchronize Rodent Reproduction with Seasons | Frontiers in Neuroendocrine Science

    Seasonal mammals use the photoperiodic variation in the nocturnal production of the pineal hormone melatonin to synchronize their reproductive activity with seasons. In rodents, the short day profile of melatonin secretion has long been proven to inhibit reproductive activity. Lately, we demonstrated that melatonin regulates the expression of the hypothalamic peptides kisspeptins (Kp) and RFamide-related peptide-3 (RFRP-3), recently discovered as potent regulators of GnRH neuron activity. In the male Syrian hamster, Kp expression in the arcuate nucleus is down-regulated by melatonin independently of the inhibitory feedback of testosterone. A central or peripheral administration of Kp induces an increase in pituitary gonadotropins and gonadal hormone secretion, but most importantly a chronic infusion of the peptide reactivates the photoinhibited reproductive axis of Syrian hamsters kept in short day conditions. RFRP-3 expression in the dorsomedial hypothalamus is also strongly inhibited by melatonin in a short day photoperiod. Although RFRP-3 is usually considered as an inhibitory component of the gonadotropic axis, a central acute administration of RFRP-3 in the male Syrian hamster induces a marked increase in gonadotropin secretion and testosterone production. Furthermore, a chronic central infusion of RFRP-3 in short day-adapted hamsters reactivates the reproductive axis, in the same manner as Kp. Both Kp and RFRP-3 neurons project onto GnRH neurons and both neuropeptides regulate GnRH neuron activity. In addition, central RFRP-3 infusion was associated with a significant increase in arcuate Kp expression. However, the actual sites of action of both peptides in the Syrian hamster brain are still unknown. Altogether our findings indicate that Kp and RFRP neurons are pivotal relays for the seasonal regulation of reproduction, and also suggest that RFRP neurons might be the primary target of the melatoninergic message.
     
  18. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Choe HK, Kim HD, Park SH, et al. Synchronous activation of gonadotropin-releasing hormone gene transcription and secretion by pulsatile kisspeptin stimulation. Proc Natl Acad Sci U S A. Synchronous activation of gonadotropin-releasing hormone gene transcription and secretion by pulsatile kisspeptin stimulation

    Pulsatile release of hypothalamic gonadotropin-releasing hormone (GnRH) is essential for pituitary gonadotrope function. Although the importance of pulsatile GnRH secretion has been recognized for several decades, the mechanisms underlying GnRH pulse generation in hypothalamic neural networks remain elusive.

    Here, we demonstrate the ultradian rhythm of GnRH gene transcription in single GnRH neurons using cultured hypothalamic slices prepared from transgenic mice expressing a GnRH promoter-driven destabilized luciferase reporter.

    Although GnRH promoter activity in each GnRH neuron exhibited an ultradian pattern of oscillations with a period of approximately 10 h, GnRH neuronal cultures exhibited partially synchronized bursts of GnRH transcriptional activity at approximately 2-h intervals. Surprisingly, pulsatile administration of kisspeptin, a potent GnRH secretagogue, evoked dramatic synchronous activation of GnRH gene transcription with robust stimulation of pulsatile GnRH secretion.

    We also addressed the issue of hierarchical interaction between the circadian and ultradian rhythms by using Bmal1-deficient mice with defective circadian clocks. The circadian molecular oscillator barely affected basal ultradian oscillation of GnRH transcription but was heavily involved in kisspeptin-evoked responses of GnRH neurons.

    In conclusion, we have clearly shown synchronous bursts of GnRH gene transcription in the hypothalamic GnRH neuronal population in association with episodic neurohormone secretion, thereby providing insight into GnRH pulse generation.
     
  19. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    Chianese R, Ciaramella V, Fasano S, Pierantoni R, Meccariello R. Kisspeptin Receptor, GPR54, as a Candidate for the Regulation of Testicular Activity in the Frog Rana esculenta. Biology of Reproduction 2013;88(3):73, 1-11. Kisspeptin Receptor, GPR54, as a Candidate for the Regulation of Testicular Activity in the Frog Rana esculenta

    Kisspeptins, acting via GPR54, are new players in the control of reproductive axis. They have the ability to communicate with GnRH neurons sending environmental, metabolic, and gonadal signals, with the induction of GnRH and LH secretion as final effect. At present, the physiological significance of kisspeptin signaling in the gonad is poorly investigated.

    We cloned GPR54 receptor from the anuran amphibian Rana esculenta testis and investigated its expression in several tissues (brain, spinal cord, ovary, muscle, and kidney). In particular, the expression analysis was carried out in pituitary and testis during the annual sexual cycle. Pituitary and testicular GPR54 mRNA increased at the end of the winter stasis (February) and reached high levels during the breeding season (April). The analysis of GPR54 expression in testis was reinforced by in situ hybridization that revealed GPR54 presence in the interstitial compartment and in proliferating germ cells. Testicular GPR54 expression in February and in June was indicated to be estradiol dependent. Furthermore, in February, kisspeptin-10 (Kp-10) induced the testicular expression of both GPR54 and estrogen receptor alpha (ERalpha) in a dose-dependent manner. Conversely, in March, Kp-10 had a biphasic effect on the expression of ERalpha, being inhibitory at short (1 h) and stimulatory at longer (4 h) incubation time.

    In conclusion, our results demonstrate that frog testis expresses GPR54 in an estradiol-dependent manner and that Kp-10 modulates the testicular expression of ERalpha; thus, the kisspeptin/GPR54 system might be locally involved in the regulation of estrogen-dependent testicular functions such as germ cell proliferation and steroidogenesis.
     
  20. Michael Scally MD

    Michael Scally MD Doctor of Medicine

    zhang c, Ronnekleiv OK, Kelly MJ. Kisspeptin inhibits a slow afterhyperpolarization current via protein kinase C and reduces spike-frequency adaptation in GnRH neurons. American Journal of Physiology - Endocrinology And Metabolism. Kisspeptin inhibits a slow afterhyperpolarization current via protein kinase C and reduces spike-frequency adaptation in GnRH neurons

    Kisspeptin signaling via its cognate receptor GPR54 in GnRH neurons plays a critical role in regulating pituitary secretion of luteininzing hormone and thus reproductive function. GPR54 is Gq-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 (TRPC) 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 (IsAHP). GnRH neurons expressed two distinct IsAHP, a kisspeptin-sensitive and an apamin-sensitive IsAHP. Essentially, kisspeptin inhibited 50% of the IsAHP and apamin inhibited the other 50% of the current. Furthermore, the kisspeptin-mediated inhibition of IsAHP was abrogated by the protein kinase C (PKC) inhibitor calphostin C, and the PKC activator phorbol 12,13-dibutyrate (PDBu) mimicked and occluded any further effects of kisspeptin on IsAHP. The protein kinase A (PKA) inhibitors H89 and Rp-cAMPS had no effect on the kisspeptin-mediated inhibition but were able to abrogate the inhibitory effects of forskolin on the IsAHP, 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 IsAHP in GnRH neurons via a PKC.