scholarly journals Nitric oxide resets kisspeptin-excited GnRH neurons via PIP2 replenishment

2020 ◽  
Vol 118 (1) ◽  
pp. e2012339118
Author(s):  
Stephanie Constantin ◽  
Daniel Reynolds ◽  
Andrew Oh ◽  
Katherine Pizano ◽  
Susan Wray
Keyword(s):  
Nitric Oxide ◽  
Transient Receptor Potential ◽  
Hormone Secretion ◽  
Brain Slices ◽  
Transient Receptor Potential Channels ◽  
Pulse Generation ◽  
Calcium Response ◽  
Nitric Oxide Signaling ◽  
Activated State ◽  
Gnrh Neurons

Fertility relies upon pulsatile release of gonadotropin-releasing hormone (GnRH) that drives pulsatile luteinizing hormone secretion. Kisspeptin (KP) neurons in the arcuate nucleus are at the center of the GnRH pulse generation and the steroid feedback control of GnRH secretion. However, KP evokes a long-lasting response in GnRH neurons that is hard to reconcile with periodic GnRH activity required to drive GnRH pulses. Using calcium imaging, we show that 1) the tetrodotoxin-insensitive calcium response evoked by KP relies upon the ongoing activity of canonical transient receptor potential channels maintaining voltage-gated calcium channels in an activated state, 2) the duration of the calcium response is determined by the rate of resynthesis of phosphatidylinositol 4,5-bisphosphate (PIP2), and 3) nitric oxide terminates the calcium response by facilitating the resynthesis of PIP2via the canonical pathway guanylyl cyclase/3′,5′-cyclic guanosine monophosphate/protein kinase G. In addition, our data indicate that exposure to nitric oxide after KP facilitates the calcium response to a subsequent KP application. This effect was replicated using electrophysiology on GnRH neurons in acute brain slices. The interplay between KP and nitric oxide signaling provides a mechanism for modulation of the refractory period of GnRH neurons after KP exposure and places nitric oxide as an important component for tonic GnRH neuronal pulses.

Tachykinin: recent developments and novel roles in health and disease

2014 ◽  
Vol 5 (3) ◽  
pp. 225-243 ◽  
Author(s):  
Takenori Onaga
Keyword(s):  
Nervous System ◽  
Transient Receptor Potential ◽  
Mammalian Species ◽  
Hormone Secretion ◽  
Transient Receptor Potential Channels ◽  
Taste Perception ◽  
Neurokinin A ◽  
Gonadotropin Secretion ◽  
Peripheral Tissues ◽  
Biological Studies

AbstractOver 80 years has passed since the discovery of substance P (SP), and a variety of peptides of the tachykinin (TK) family have been found and investigated. SP, neurokinin A (NKA), and neurokinin B (NKB) are representative peptides in mammalian species. SP and NKA are major excitatory neurotransmitters in the peripheral nervous system, while NKB is primarily involved in the central nervous system (CNS). Moreover, TK peptides play roles not only as neurotransmitters but also as local factors and are involved in almost all aspects of the regulation of physiological functions and pathophysiological processes. The role of SP as a mediator of pain processing and inflammation in peripheral tissues in coordination with transient receptor potential channels is well established, while novel aspects of TKs in relation to hematopoiesis, venous thromboembolism, tendinopathy, and taste perception have been clarified. In the CNS, the NKB signaling system in the hypothalamus has been shown to play a crucial role in the regulation of gonadotropin hormone secretion and the onset of puberty, and molecular biological studies have elucidated novel prophylaxic activities of TKs against neurogenic movement disorders based on their molecular structure. This review provides an overview of the novel aspects of TKs reported around the world in the last 5 years, with particular focus on nociception, inflammation, hemopoiesis, gonadotropin secretion, and CNS diseases.

Insulin-like growth factor 1 (IGF-1) increases GABAergic neurotransmission to GnRH neurons via suppressing the retrograde tonic endocannabinoid signaling pathway in mice

2020 ◽  
Author(s):  
Flora Balint ◽  
Veronika Csillag ◽  
Csaba Vastagh ◽  
Zsolt Liposits ◽  
Imre Farkas
Keyword(s):  
Growth Factor ◽  
Transient Receptor Potential ◽  
Brain Slices ◽  
Fine Tuning ◽  
Transient Receptor Potential Vanilloid ◽  
Insulin Like Growth Factor ◽  
Gabaergic Neurotransmission ◽  
Postsynaptic Currents ◽  
Gnrh Neurons

Introduction: Hypophysiotropic gonadotropin releasing-hormone (GnRH) neurons orchestrate various physiological events that control the onset of puberty. Previous studies showed that insulin-like growth factor 1 (IGF-1) induces the secretion of GnRH and accelerates the onset of puberty, suggesting a regulatory role of this hormone upon GnRH neurons. Methods: To reveal responsiveness of GnRH neurons to IGF-1 and elucidate molecular pathways acting downstream to the IGF-1 receptor (IGF-1R), in vitro electrophysiological experiments were carried out on GnRH-GFP neurons in acute brain slices from prepubertal (23-29 days) and pubertal (50-day) male mice. Results: Administration of IGF-1 (13 nM) significantly increased the firing rate and frequency of spontaneous postsynaptic currents (sPSCs), and that of excitatory GABAergic miniature postsynaptic currents (mPSCs). No GABAergic mPSCs were induced by IGF-1 in the presence of GABAA-R blocker picrotoxin. The increase in the mPSC frequency was prevented by the use of IGF-1R antagonist, JB1 (1 µM) or the intracellularly applied PI3K blocker (LY294002, 50 µM) showing involvement of IGF-1R and PI3K in the mechanism. Blockade of the transient receptor potential vanilloid 1 (TRPV1), an element of the tonic retrograde endocannabinoid machinery by AMG9810 (10 µM) or antagonizing cannabinoid receptor type-1 (CB1) by AM251 (1 µM) abolished the effect. Discussion/Conclusion: These findings indicate that IGF-1 arrests the tonic retrograde endocannabinoid pathway in GnRH neurons and this disinhibition increases the release of GABA from presynaptic terminals that, in turn, activates GnRH neurons leading to the fine-tuning of the hypothalamo-pituitary-gonadal axis.

scholarly journals Kisspeptin inhibits a slow afterhyperpolarization current via protein kinase C and reduces spike frequency adaptation in GnRH neurons

2013 ◽  
Vol 304 (11) ◽  
pp. E1237-E1244 ◽  
Author(s):  
Chunguang Zhang ◽  
Oline K. Rønnekleiv ◽  
Martin J. Kelly
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Transient Receptor Potential ◽  
Critical Role ◽  
Transient Receptor Potential Channels ◽  
Spike Frequency ◽  
Spike Frequency Adaptation ◽  
Kinase C ◽  
Frequency Adaptation ◽  
Gnrh Neurons

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 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 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 mimicked and occluded any further effects of kisspeptin on IsAHP. 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 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.

scholarly journals Activation of Neuronal Nitric Oxide Release Inhibits Spontaneous Firing in Adult Gonadotropin-Releasing Hormone Neurons: A Possible Local Synchronizing Signal

Endocrinology ◽  
2007 ◽  
Vol 149 (2) ◽  
pp. 587-596 ◽  
Author(s):  
Jérôme Clasadonte ◽  
Pierre Poulain ◽  
Jean-Claude Beauvillain ◽  
Vincent Prevot
Keyword(s):  
Nitric Oxide ◽  
Neuronal Activity ◽  
Brain Slices ◽  
No Synthase ◽  
Membrane Properties ◽  
No Production ◽  
Spontaneous Firing ◽  
Preoptic Region ◽  
Gnrh Neurons ◽  
Bursting Activity

The activation of nitric oxide (NO) signaling pathways in hypothalamic neurons plays a key role in the control of GnRH secretion that is central to reproductive function. It is unknown whether NO directly modulates the firing behavior of GnRH neurons in the preoptic region of the mature brain. Using patch-clamp recordings from GnRH neurons expressing green fluorescent protein in adult mice brain slices, we demonstrate that the NO precursor, l-arginine (Arg), or the NO donor, diethylamine/NO, induced a robust and reversible reduction in the spontaneous firing activity of GnRH neurons, including bursting activity. The effects of l-Arg were prevented by the NO synthase inhibitor Nω-nitro-l-Arg methyl ester hydrochloride. Histochemical studies revealing a close anatomical relationship between neurons producing NO and GnRH perikarya, together with the loss of the l-Arg-mediated inhibition of GnRH neuronal activity via the selective blockade of neuronal NO synthase, suggested that the primary source of local NO production in the mouse preoptic region was neuronal. Synaptic transmission uncoupling did not alter the effect of NO, suggesting that NO affects the firing pattern of GnRH neurons by acting at a postsynaptic site. We also show that the NO-mediated changes in membrane properties in the GnRH neurons require soluble guanylyl cyclase activity and may involve potassium conductance. By revealing that NO is a direct modulator of GnRH neuronal activity, our results introduce the intriguing possibility that this gaseous neurotransmitter may be used by the sexual brain to modulate burst firing patterns. It may set into phase the bursting activity of GnRH neurons at key stages of reproductive physiology.

scholarly journals Emerging Roles for Ion Channels in Ovarian Cancer: Pathomechanisms and Pharmacological Treatment

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 668
Author(s):  
Concetta Altamura ◽  
Maria Raffaella Greco ◽  
Maria Rosaria Carratù ◽  
Rosa Angela Cardone ◽  
Jean-François Desaphy
Keyword(s):  
Ovarian Cancer ◽  
Ion Channels ◽  
Transient Receptor Potential ◽  
Critical Role ◽  
Gynecologic Cancer ◽  
Receptor Potential ◽  
Transient Receptor Potential Channels ◽  
Platinum Resistance

Ovarian cancer (OC) is the deadliest gynecologic cancer, due to late diagnosis, development of platinum resistance, and inadequate alternative therapy. It has been demonstrated that membrane ion channels play important roles in cancer processes, including cell proliferation, apoptosis, motility, and invasion. Here, we review the contribution of ion channels in the development and progression of OC, evaluating their potential in clinical management. Increased expression of voltage-gated and epithelial sodium channels has been detected in OC cells and tissues and shown to be involved in cancer proliferation and invasion. Potassium and calcium channels have been found to play a critical role in the control of cell cycle and in the resistance to apoptosis, promoting tumor growth and recurrence. Overexpression of chloride and transient receptor potential channels was found both in vitro and in vivo, supporting their contribution to OC. Furthermore, ion channels have been shown to influence the sensitivity of OC cells to neoplastic drugs, suggesting a critical role in chemotherapy resistance. The study of ion channels expression and function in OC can improve our understanding of pathophysiology and pave the way for identifying ion channels as potential targets for tumor diagnosis and treatment.

scholarly journals Intractable Itch in Atopic Dermatitis: Causes and Treatments

Biomedicines ◽  
2021 ◽  
Vol 9 (3) ◽  
pp. 229
Author(s):  
Yoshie Umehara ◽  
Chanisa Kiatsurayanon ◽  
Juan Valentin Trujillo-Paez ◽  
Panjit Chieosilapatham ◽  
Ge Peng ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Atopic Dermatitis ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Clinical Problem ◽  
Transient Receptor Potential Channels ◽  
Protease Activated Receptors ◽  
H1 Antihistamines ◽  
Potential Channels

Itch or pruritus is the hallmark of atopic dermatitis and is defined as an unpleasant sensation that evokes the desire to scratch. It is also believed that itch is a signal of danger from various environmental factors or physiological abnormalities. Because histamine is a well-known substance inducing itch, H1-antihistamines are the most frequently used drugs to treat pruritus. However, H1-antihistamines are not fully effective against intractable itch in patients with atopic dermatitis. Given that intractable itch is a clinical problem that markedly decreases quality of life, its treatment in atopic dermatitis is of high importance. Histamine-independent itch may be elicited by various pruritogens, including proteases, cytokines, neuropeptides, lipids, and opioids, and their cognate receptors, such as protease-activated receptors, cytokine receptors, Mas-related G protein-coupled receptors, opioid receptors, and transient receptor potential channels. In addition, cutaneous hyperinnervation is partly involved in itch sensitization in the periphery. It is believed that dry skin is a key feature of intractable itch in atopic dermatitis. Treatment of the underlying conditions that cause itch is necessary to improve the quality of life of patients with atopic dermatitis. This review describes current insights into the pathophysiology of itch and its treatment in atopic dermatitis.

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