Voltage-Gated Potassium Currents Are Targets of Diurnal Changes in Estradiol Feedback Regulation and Kisspeptin Action on Gonadotropin-Releasing Hormone Neurons in Mice

Article (PDF Available)inBiology of Reproduction 85(5):987-95 · July 2011with22 Reads
DOI: 10.1095/biolreprod.111.093492 · Source: PubMed
Estradiol has both negative and positive feedback actions upon gonadotropin-releasing hormone (GnRH) release; the latter actions trigger the preovulatory GnRH surge. Although neurobiological mechanisms of the transitions between feedback modes are becoming better understood, the roles of voltage-gated potassium currents, major contributors to neuronal excitability, are unknown. Estradiol alters two components of potassium currents in these cells: a transient current, I(A), and a sustained current, I(K). Kisspeptin is a potential mediator between estradiol and GnRH neurons and can act directly on GnRH neurons. We examined how estradiol, time of day, and kisspeptin interact to regulate these conductances in a mouse model exhibiting daily switches between estradiol negative (morning) and positive feedback (evening). Whole-cell voltage clamp recordings were made from GnRH neurons in brain slices from ovariectomized (OVX) mice and from OVX mice treated with estradiol (OVX+E). There were no diurnal changes in either I(A) or I(K) in GnRH neurons from OVX mice. In contrast, in GnRH neurons from OVX+E mice, I(A) and I(K) were greater during the morning when GnRH neuron activity is low and smaller in the evening when GnRH neuron activity is high. Estradiol increased I(A) in the morning and decreased it in the evening, relative to that in cells from OVX mice. Exogenously applied kisspeptin reduced I(A) regardless of time of day or estradiol status. Estradiol, interacting with time of day, and kisspeptin both depolarized I(A) activation. These findings extend our understanding of both the neurobiological mechanisms of estradiol negative vs. positive regulation of GnRH neurons and of kisspeptin action on these cells.
    • "Precisely how kisspeptin closes K ir channels in GnRH neurons is unclear although it is presumed to occur through the Gpr54 Ga q -PLC signaling pathway and may involve phosphatidylinositol-4,5-bisphosphate (PIP2) (Zhang et al., 2008Zhang et al., , 2013a). Evidence has also been presented suggesting a minor role for A-type potassium channels in the kisspeptin activation of GnRH neurons (Pielecka-Fortuna et al., 2011) (Fig. 2). The molecularly uncharacterized potassium channels underlying the slow afterhyperpolarization currents in GnRH neurons (Lee et al., 2010) have also been suggested recently to be modulated by Gpr54 activation to allow GnRH neurons to exhibit their typical prolonged and sustained firing patterns following kisspeptin depolarization (Zhang et al., 2013b) (Fig. 2). "
    [Show abstract] [Hide abstract] ABSTRACT: Kisspeptin neurons are critical components of the neuronal network controlling the activity of the gonadotropin-releasing hormone (GnRH) neurons. A variety of genetically-manipulated mouse models have recently facilitated the study of the electrical activity of the two principal kisspeptin neuron populations located in the rostral periventricular area of the third ventricle (RP3V) and arcuate nucleus (ARN) in acute brain slices. We discuss here the mechanisms and pathways through which kisspeptin neurons regulate GnRH neuron activity. We then examine the different kisspeptin-green fluorescent protein mouse models being used for kisspeptin electrophysiology and the data obtained to date for RP3V and ARN kisspeptin neurons. In light of these new observations on the spontaneous firing rates, intrinsic membrane properties, and neurotransmitter regulation of kisspeptin neurons, we speculate on the physiological roles of the different kisspeptin populations.
    Full-text · Article · Jun 2014
    • "Although ovariectomized mice show no diurnal variations in either I A or I K in GnRH neurons, estradiol administration induces higher I A and I K in the morning at reduced neuronal activity but causes lower I A and I K in the evening at increased neuronal activity. On the other hand, the addition of kisspeptin (mediating the estradiol effects in GnRH neurons) suppresses the I A independently of the time of the day [249]. Both BK Ca and K v participate in estradiol stimulated vasodilatation and in the consequent stabilization of blood pressure [237]. "
    [Show abstract] [Hide abstract] ABSTRACT: This review is focused on the physiological and pathophysiological relevance of steroids influencing the activities of the central and peripheral nervous systems with regard to their concentrations in body fluids and tissues in various stages of human life like the fetal development or pregnancy. The data summarized in this review shows that DHEA and its unconjugated and sulfated metabolites are physiologically and pathophysiologically relevant in modulating numerous ion channels and participate in vital functions of the human organism. DHEA and its unconjugated and sulfated metabolites including 5α/β-reduced androstane steroids participate in various physiological and pathophysiological processes like the management of GnRH cyclic release, regulation of glandular and neurotransmitter secretions, maintenance of glucose homeostasis on one hand and insulin insensitivity on the other hand, control of skeletal muscle and smooth muscle activities including vasoregulation, promotion of tolerance to ischemia and other neuroprotective effects. In respect of prevalence of steroid sulfates over unconjugated steroids in the periphery and the opposite situation in the CNS, the sulfated androgens and androgen metabolites reach relevance in peripheral organs. The unconjugated androgens and estrogens are relevant in periphery and so much the more in the CNS due to higher concentrations of most unconjugated steroids in the CNS tissues than in circulation and peripheral organs.
    Full-text · Article · May 2014
    • "Kisspeptins act on the majority of GnRH neurons to initiate a sustained depolarization event and increase the action potential firing rate555657. Pharmacological studies and an assessment of the current–voltage (I–V) relationships [57, 58] and activation of canonical transient receptor potential channels (TRPC) [56, 59]. Indeed, individual GnRH neurons have been shown by RT-PCR to express several TRPC channel subunits [59]. "
    [Show abstract] [Hide abstract] ABSTRACT: Kisspeptins are a family of overlapping neuropeptides, encoded by the Kiss1 gene, that are required for activation and maintenance of the mammalian reproductive axis. Kisspeptins act within the hypothalamus to stimulate release of gonadotrophic releasing hormone and activation of the pituitary-gonadal axis. Robust model systems are required to dissect the regulatory mechanisms that control Kiss1 neuronal activity and to examine the molecular consequences of kisspeptin signalling. While studies in normal animals have been important in this, transgenic mice with targeted mutations affecting the kisspeptin signalling pathway have played a significant role in extending our understanding of kisspeptin physiology. Knock-out mice recapitulate the reproductive defects associated with mutations in humans and provide an experimentally tractable model system to interrogate regulatory feedback mechanisms. In addition, transgenic mice with cell-specific expression of modulator proteins such as the CRE recombinase or fluorescent reporter proteins such as GFP allow more sophisticated analyses such as cell or gene ablation or electrophysiological profiling. At a less complex level, immortalized cell lines have been useful for studying the role of kisspeptin in cell migration and metastasis and examining the intracellular signalling events associated with kisspeptin signalling.
    Full-text · Article · Apr 2013
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