Revista Bionatura
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Beyond reproduction: Exploring the Non-Canonical roles of the Kisspeptin System in Diverse Biological Systems
Deisy Yurley Rodríguez Sarmiento1*
1  Medicine Program, Faculty of Health Sciences, Universidad Autonoma de Bucaramanga;
* Correspondence: [email protected]
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G protein-coupled receptors are integral membrane proteins in cell signaling processes. Activation of G protein-coupled receptors by specific agonists promotes the activation of different G-proteins, activating different intracellular signaling pathways, including adenylate cyclase activation and intracellular calcium release. One of the G protein-coupled receptors studied is the kisspeptin receptor, which regulates reproduction and gonadotropin secretion. However, recent studies have shown that kisspeptin and its receptor have non-canonical roles in cell signaling and several biological systems. In the present review, we will present these different functions exerted by the kisspeptin system in different biological systems, such as the central nervous system, the cardiovascular system, and the immune system, as well as the role of this system in pathologies such as preeclampsia, diabetes, and cancer. Understanding their non-canonical roles in cell signaling may have important implications in developing new therapies for various diseases.
Keywords: Kisspeptin-1 Receptor, Kisspeptins, G-protein coupled receptor, Signal Transduction, Cancer, Diabetes Mellitus, Preeclampsia.

Kisspeptins are a family of related peptides identified as the natural ligands of the G protein-coupled receptor (GPCR) GPR541-3, also known as the kisspeptin receptor (KISS1R). The physiological ligand for the KISS1R receptor was identified by several groups in 20012-4 and is encoded by the KISS1 gene, which produces a 145 amino acid protein, Kisspeptin54 (KP-54), also known as metastin (Figure 1). The C-terminal region of KP-54 is responsible for binding to the receptor, and this region is the most conserved among different species. The peptides in this 10-, 13- and 14-amino acid portion (KP-10, KP-13, and KP-14) exhibit similar activities at the Kiss1R receptor in vitro assays2-4.  

Figure 1. Production of kisspetins. The primary protein product of the KISS1 gene is cleaved (triangles) to produce small amidated peptides (kisspeptins, Kp) capable of binding to the GPR54 receptor. All peptides containing the same C-terminal portion are biologically active. Source: Author.

The kisspeptin-KISS1R system plays an essential role in the neuroendocrine control of the reproductive axis5. However, in recent years, the kisspeptin system has also been found to be involved in various biological processes non-related to reproduction. These non-canonical roles of kisspeptin have been identified in multiple methods, including the cardiovascular system 6, central nervous system 7, immune system 8, preeclampsia9, diabetes10, and cancer11.
Non-canonical signaling refers to biological effects that occur through pathways other than classical GPCR signaling. In the case of the kisspeptin system, these effects may be mediated by the activation of sex hormone receptors12, translation factors13, and ionic channels14. It has also been shown that kisspeptin can interact with other signaling systems, such as the insulin signaling system and the insulin-like growth factor (IGF) system15. The precise mechanisms of kisspeptin non-canonical signaling and its physiological effects have yet to be fully elucidate and are still under study.
In this review, recent findings on the non-canonical roles of kisspeptin in various biological systems, including the cardiovascular system, central nervous system, preeclampsia, immune system, diabetes, and cancer, will be presented. In addition, possible underlying mechanisms of non-canonical kisspeptin signaling and their potential clinical significance will be discussed.
Non-Canonical Signaling of Kisspeptins
Studies have revealed that Kisspeptins, primarily acting via the KISS1R receptor, activate the Gq/11 protein, increasing intracellular calcium through PLC activation2. Also, kisspeptins can activate critical non-canonical pathways, allowing us to understand the complexity of the signaling processes. One of the most studied examples of non-canonical kisspeptin signaling is the activation of the ERK1/2 signaling pathway through the direct binding of kisspeptin to the MET tyrosine kinase receptor16, and this signaling pathway has been implicated in promoting progesterone secretion. Also, according to a study conducted by Kim and Cho13, the activation of EIF2AK2 induced by kisspeptin may require the presence of RhoA. This suggests that the signaling pathway responsible for the effects of kisspeptin may be illustrated by the sequence KISS1R/Gq/11/p63RhoGEF/RhoA/EIF2AK2. This signaling pathway leads to inhibit cancer growth and metastasis.
In addition, it has been shown that kisspeptin can activate the Ca2+ mobilization and cAMP reduction levels through interaction with receptors for other ligands, such as Neuropeptide FF receptors (NPFFR1 and NPFFR2)17, with highly potent activity leading to the possible localization of a secondary kisspeptin receptors such as NPFFRs (Figure 2.).
In summary, non-canonical cell signaling of the kisspeptin system is an emerging area of research that may have essential implications in regulating physiological and pathological function. Although several non-canonical signaling pathways activated by kisspeptin have been identified, further studies are needed to understand their role in regulating physiology and pathology.

Figure 2. Distinct signaling pathways are triggered following the activation of the Kiss1 receptor by the endogenous agonist's KPs. The canonical KISS1 receptor signal transduction pathways triggered by the endogenous agonist KPs include coupling to the Gq-protein with the activation of PLC, which processes the membrane PIP2 to produce IP3 and DAG. IP3 interacts with IP3 receptors (IP3R) at the endoplasmic reticulum and releases Ca2+, which, together with DAG, leads to PKC activation. In the non-canonical signaling pathway, KPs bind to NPFFR receptors, activating two Gq- and Gi/o-dependent signaling that promote an increase in intracellular calcium and a decrease in cAMP concentration.
Non-Canonical Roles of Kisspeptins
Kisspeptins and the Cardiovascular System
The kisspeptin system is a peptide signaling important in regulating reproduction, appetite, metabolism and energy homeostasis.2-4. In addition, the kisspeptin system has also been shown to be involved in regulating cardiovascular function.
Kisspeptin and its receptor KISS1R can be found in endothelial cells, vascular smooth muscle, and other cardiovascular tissues, including the aortic artery 18. In the isolated human coronary artery and umbilical vein, it was observed that KP-10, KP-13, and KP-54 act as powerful vasoconstrictors. The response of these tissues to KP was similar to that of angiotensin (AngII) in the coronary artery, as reported in that study18.
Also, in 2011, Maguire et al. showed that kisspeptins are a potent positive inotrope in the atria of humans, rats, and mice19. KP-10 vascular effects are considered significant due to hypertension and edema as symptoms of preeclampsia in late-term pregnancies, which subside after delivery.
In summary, understanding the potential "off-target" cardiovascular effects can guide the development and usage of kisspeptin-derived treatments, such as improved analogs and antagonists with increased efficacy21.
Kisspeptins and Preeclampsia
Preeclampsia is a pregnancy complication that involves high blood pressure and dysfunction of the body's endothelial cells. Studies suggest that changes in the levels of KISS1 and KISS1R, both at the mRNA and protein levels, may be responsible for causing preeclampsia. These changes lead to a decrease in KISS1 expression and an increase in KISS1R expression compared to a normal, healthy pregnancy22. Kisspeptin is expressed in the placenta and has been shown to play an essential role in regulating fetal growth and development23, as well as in angiogenesis and placental endothelial function23 24. In addition, lower levels of plasma kisspeptin-10 have been associated with more severe forms of the disease25.
Kisspeptin may play a role in the development of preeclampsia by inhibiting the growth of new vessels from placental vessels24. A clinical study demonstrated that women with preeclampsia had lower levels of plasma kisspeptin-10, which was inversely correlated with the severity of their condition. Maternal plasma KP-10 levels were also associated with estimated fetal weight during the second and third trimesters26. Another study found that kisspeptin levels at 16 weeks in maternal plasma were positively correlated with the birthweight of fetuses in uncomplicated pregnancies27. The results indicate that plasma levels of kisspeptin may function as a biomarker of insufficient blood flow to the uterus and placenta, along with limited fetal development within the uterus, lead to restricted growth.
Kisspeptins and the Central Nervous System
Several lines of evidence indicate kisspeptin directly affects Gonadotropin hormone-releasing Hormone (GnRH) neurons. Firstly, most GnRH neurons express KISS1R28. Furthermore, the fibers of KISS1R are close to GnRH neurons and stimulate the release of gonadotropin-releasing hormone by activating multiple ion channels through a pathway dependent on phospholipase C and calcium29. Thirdly, kisspeptin can directly depolarize and increase the firing rates of GnRH neurons in vitro28. It is important to note that kisspeptin may not only act through traditional synaptic mechanisms to stimulate GnRH secretion but also directly in a non-synaptic manner, especially in the median eminence30. Increasing evidence suggests that kisspeptin also affects intermediary neurons, such as GABAergic cells, to regulate GnRH secretion 31,32.
Additionally, the study conducted by Khonacha et al. demonstrated that KP-13 can enhance spatial memory consolidation and retrieval. Also, when administered in the presence of Amiloid β (Aβ), KP-13 significantly improved reference memory impairment caused by Aβ. These findings suggest that KP-13, as a neuropeptide, may possess neuroprotective properties against amyloid-beta-induced pathology and has the potential to enhance spatial memory33.
Kisspeptins and the Immune System
Due to the expression of kisspeptin receptors on various immune system cells 2-4, it has been proposed that kisspeptin, in conjunction with other pregnancy hormones and proteins, has the potential to regulate immune responses. Also, kisspeptin may play a role in regulating cytokines, which are proteins that control the immune response and can be regulated through modulation of their production. In particular, it has been shown that kisspeptin can increase the production of anti-inflammatory cytokines such as interleukin-10 (IL-10) and decrease the production of proinflammatory cytokines such as interleukin-17A (IL-17A)8.
Studies on the immune system response to kisspeptin have covered how the hormone regulates CD4+T lymphocytes through molecular mechanisms35. By binding to KISS1R, kisspeptin increases intracellular cAMP concentrations, boosting iTreg production and the quantity of these cells in the culture. The heightened cAMP also activates cAMP response element binding protein (CREB) and MAPK/ERK (MEK1/2)36, which helps CD4+ lymphocytes differentiate into iTreg and reduces RORC expression. The capacity of [Ca2+] governs the control of the cAMP-dependent activity of kisspeptin in lymphoid cells I to trigger protein kinase A (PKA) through Ca2+/CaM, Ca2+/CaM dependent protein kinase 2 (CaMKK2), and AMP-activated protein kinase (AMPK)37. PKA, in turn, inhibits mTOR38, which activates RORC transcription39 and phosphorylates CREB 40. The role of kisspeptin in coordinating reproductive and immune functions may help to discover new mechanisms of this control system.
Kisspeptins and Diabetes
Diabetes is a long-term condition marked by high glucose levels in the blood. This occurs either because the pancreas does not produce enough insulin or because it is resistant to the effects of insulin, a hormone responsible for regulating blood glucose levels. The kisspeptin system has been interested in diabetes because it regulates energy metabolism and pancreatic function10