Types Of Histamine Receptors Research Articles

An Overview of Antihistamines and their Properties used for Treatment of Different Diseases.

By comparing the histamine impact to the instant response to an injected foreign protein in previously sensitized animals, one might hypothesize that histamine may be involved in this reaction. Through all four of the recognized types of histamine receptors, histamine is also essential for the control of immunological function and acute and chronic allergic inflammation. Recent evidence points to anti-IgE antibodies and specific antibodies to cytokines like IL-4 or IL-5 that are associated with allergic inflammation as probable causes of Allergic Rhinitis. The therapeutic advantage of antihistamines is a decrease in allergy symptoms and any other allergy-related symptoms. We research the many diseases and dose forms in which antihistamines are used. Pediatric age groups have never been thoroughly studied for firstgeneration antihistamines. Oral antihistamines are suggested as the first line of therapy for people with mild to severe intermittent Allergic Rhinitis symptoms. Currently, approximately 100 different antihistamine-containing medicines and around 20 different H1-receptor antagonists are available for therapeutic use. Antihistamines of the second generation are more efficient and secure than those of the first generation. We conducted a research on the sedative and non-sedative effects of antihistamines used to treat various diseases. The present investigation highlights the use of antihistamines in various diseases at different ages, their sedative and non-sedative effect, and their utility in treating insomnia based on their safety and current use among the patient population, as well as our observation.

Histamine and Its Receptors in the Mammalian Inner Ear: A Scoping Review.

Histamine is a widely distributed biogenic amine with multiple biological functions mediated by specific receptors that determine the local effects of histamine. This review aims to summarize the published findings on the expression and functional roles of histamine receptors in the inner ear and to identify potential research hotspots and gaps. A search of the electronic databases PubMed, Web of Science, and OVID EMBASE was performed using the keywords histamine, cochlea*, and inner ear. Of the 181 studies identified, 18 eligible publications were included in the full-text analysis. All four types of histamine receptors were identified in the mammalian inner ear. The functional studies of histamine in the inner ear were mainly in vitro. Clinical evidence suggests that histamine and its receptors may play a role in Ménière's disease, but the exact mechanism is not fully understood. The effects of histamine on hearing development remain unclear. Existing studies have successfully determined the expression of all four histamine receptors in the mammalian inner ear. However, further functional studies are needed to explore the potential of histamine receptors as targets for the treatment of hearing and balance disorders.

Ergometrine stimulates histamine H2 receptors in the isolated human atrium

Ergometrine (6aR,9R)-N-((S)-1-hydroxypropan-2-yl)-7-methyl-4,6,6a,7,8,9-hexa-hydro-indolo-[4,3-fg]chinolin-9-carboxamide or lysergide acid β-ethanolamide or ergonovine) activates several types of serotonin and histamine receptors in the animal heart. We thus examined whether ergometrine can activate human serotonin 5-HT4 receptors (h5-HT4R) and/or human histamine H2 receptors (hH2R) in the heart of transgenic mice and/or in the human isolated atrium. Force of contraction or beating rates were studied in electrically stimulated left atrial or spontaneously beating right atrial preparations or spontaneously beating isolated retrogradely perfused hearts (Langendorff setup) of mice with cardiac specific overexpression of the h5-HT4R (5-HT4-TG) or of mice with cardiac specific overexpression of the hH2R (H2-TG) or in electrically stimulated human right atrial preparations obtained during cardiac surgery. Western blots to assess phospholamban (PLB) phosphorylation on serine 16 were performed. Ergometrine exerted concentration- and time-dependent positive inotropic effects and positive chronotropic effects in atrial preparations starting at 0.3 µM and reaching a plateau at 10 µM in H2-TGs (n = 7). This was accompanied by an increase in PLB phosphorylation at serine 16. Ergometrine up 10 µM failed to increase force of contraction in left atrial preparations from 5-HT4-TGs (n = 5). Ten micrometer ergometrine increased the force of contraction in isolated retrogradely perfused spontaneously beating heart preparations (Langendorff setup) from H2-TG but not 5-HT4-TG. In the presence of the phosphodiesterase inhibitor cilostamide (1 µM), ergometrine at 10 µM exerted positive inotropic effects in isolated electrically stimulated human right atrial preparations, obtained during cardiac surgery, and these effects were eliminated by 10 µM of the H2R antagonist cimetidine but not by 10 µM of the 5-HT4R antagonist tropisetron. Furthermore, ergometrine showed binding to human histamine H2 receptors (at 100 µM and 1 mM) using HEK cells in a recombinant expression system (pKi < 4.5, n = 3). In conclusion, we suggest that ergometrine is an agonist at cardiac human H2Rs.

Unraveling the venom chemistry with evidence for histamine as key regulator in the envenomation by caterpillar Automeris zaruma.

Over the past decades, envenomation by caterpillars of Automeris spp. became an increasing health problem in Latin America. Accidental contact with the stinging spines of these caterpillars cause acute local pain, itching, inflammation and skin rashes that persists for days. Even when the cause is obvious, the exact molecular mechanisms responsible for the observed symptoms are yet to be elucidated. Here, we describe for the first time, an active compound in the venom and the study of the bioactivity of the venom extracted from the spines of the caterpillar Automeris zaruma. Electrophysiological screening of a library of membrane proteins important for pain and itch enabled us to investigate and reveal the mode of action of the venom of A. zaruma. Further mass spectrometric analysis (Q-TOF-MS) made it possible to establish a link between the bioactivity and the components found in the venom. We show that the spine extract of A. zaruma contains histamine that potently activates the four types of the human histamine receptors (H1R, H2R, H3R and H4R) with a selectivity preference towards H3R and H4R. Furthermore, a modulation of the target MRGPRX2 was found. Together, these findings are the first to explain the symptomology of A. zaruma envenomation, enabling us a better understanding of caterpillar envenomation and predict that the hurdle of the scarce efficacy of the currently used antihistaminic drugs can be overcome by including H3R and H4R blockers in the clinical used medication. Such an approach might be used for other caterpillar envenomation in the world and represent a significant improvement for the well-being of the patient.

Food Intolerance: The Role of Histamine.

Histamine is a natural amine derived from L-histidine. Although it seems that our knowledge about this molecule is wide and diverse, the importance of histamine in many regulatory processes is still enigmatic. The interplay between different types of histamine receptors and the compound may cause ample effects, including histamine intoxication and so-called histamine intolerance or non-allergic food intolerance, leading to disturbances in immune regulation, manifestation of gastroenterological symptoms, and neurological diseases. Most cases of clinical manifestations of histamine intolerance are non-specific due to tissue-specific distribution of different histamine receptors and the lack of reproducible and reliable diagnostic markers. The diagnosis of histamine intolerance is fraught with difficulties, in addition to challenges related to the selection of a proper treatment strategy, the regular course of recovery, and reduced amelioration of chronic symptoms due to inappropriate treatment prescription. Here, we reviewed a history of histamine uptake starting from the current knowledge about its degradation and the prevalence of histamine precursors in daily food, and continuing with the receptor interactions after entering and the impacts on the immune, central nervous, and gastrointestinal systems. The purpose of this review is to build an extraordinarily specific method of histamine cycle assessment in regard to non-allergic intolerance and its possible dire consequences that can be suffered.

Antihistamínicos en el tratamiento de la urticaria en México

There are four types of histamine receptors. Allergic symptoms, especially those in rhinoconjunctivitis and urticaria, are mainly caused by activation of histamine receptor 1 (H1). Consequently, oral H1-antihistamines form and integral part of the treatment of these diseases. Antihistamines are inverse agonists that stabilize the non-active configuration of the histamine receptor. First generation H1-antihistamines cause a variety of adverse effects via several mechanisms: sedation (accumulation in the central nervous system), dry mouth, urinary retention, weight gain (low selectivity: stimulation of serotonin/muscarinic/alpha-adrenergic receptors) and drug interactions (substrate of CYP450-3A4). Generally second generation H1-antihistamines have a better safety profile. New guidelines on allergic rhinitis and urticaria recommend second generation H1-antihistamines as first line drugs, with -if necessary- four-times updosing to obtain control in urticaria. The enhanced efficacy of quadruple doses in urticaria, while maintaining a good safety profile, has been shown for bilastine, desloratadine and levocetirizine (rupatadine). For ebastine and fexofenadine only the safety of quadruple doses has been shown till now. Extreme precaution should be taken with astemizol and terfenadine that never should be up-dosed, as high serum concentrations can cause potentially fatal ventricular tachycardia. First generation antihistamines are not recommended as first line treatment and updosing is not safe.

Chapter 24 - The tuberomamillary nucleus in neuropsychiatric disorders

The tuberomamillary nucleus (TMN) is located within the posterior part of the hypothalamus. The histamine neurons in it synthesize histamine by means of the key enzyme histidine decarboxylase (HDC) and from the TMN, innervate a large number of brain areas, such as the cerebral cortex, hippocampus, amygdala as well as the thalamus, hypothalamus, and basal ganglia. Brain histamine is reduced to an inactivated form, tele-methylhistamine (t-MeHA), by histamine N-methyltransferase (HMT). In total, there are four types of histamine receptors (H1-4Rs) in the brain, all of which are G-protein coupled. The histaminergic system controls several basal physiological functions, including the sleep-wake cycle, energy and endocrine homeostasis, sensory and motor functions, and cognitive functions such as attention, learning, and memory. Histaminergic dysfunction may contribute to clinical disorders such as Parkinson's disease, Alzheimer's disease, Huntington's disease, narcolepsy type 1, schizophrenia, Tourette syndrome, and autism spectrum disorder. In the current chapter, we focus on the role of the histaminergic system in these neurological/neuropsychiatric disorders. For each disorder, we first discuss human data, including genetic, postmortem brain, and cerebrospinal fluid studies. Then, we try to interpret the human changes by reviewing related animal studies and end by discussing, if present, recent progress in clinical studies on novel histamine-related therapeutic strategies.

Histamine

Histamine has at least twenty-three known physiological functions, including playing a prominent role in immunologically mediated inflammation. The structure and metabolism of histamine is discussed, together with the various types of histamine receptors. Histamine plays a role in anaphylaxis, mast cell activation syndromes and mastocytosis and these conditions are relevant to anaesthetic practice. The antihistamine drugs and the H2 receptors agonists are discussed with regard to their role in anaesthesia.

Histamine Induces Microglia Activation and the Release of Proinflammatory Mediators in Rat Brain Via H1R or H4R.

Histamine is a major peripheral inflammatory mediator and a neurotransmitter in the central nervous system. We have reported that histamine induces microglia activation and releases proinflammatory factors in primary cultured microglia. Whether histamine has similar effects in vivo is unknown. In the present study, we aimed to investigate the role of histamine and its receptors in the release of inflammatory mediators and activation of microglia in rat brain. We site-directed injected histamine, histamine receptor agonists or histamine receptor antagonists in the rat lateral ventricle using stereotaxic techniques. Flow cytometry was employed to determine histamine receptor expression in rat microglia. Microglia activation was assessed by Iba1 immunohistochemistry. The levels of tumour necrosis factor-alpha (TNF-α), interleukin-1beta (IL-1β) and interleukin-10 (IL-10) were measured with commercial enzyme-linked immunosorbent assay (ELISA) kits, TNF-α, IL-1β and IL-10 mRNA expressions were determined with Quantitative Real-Time Polymerase Chain Reaction (qRT-PCR). We found that all four types of histamine receptors were expressed in rat brain microglia. Histamine was able to induce microglia activation and subsequent production of the inflammatory factors TNF-α, IL-1β and IL-10, and these effects were partially abolished by H1R and H4R antagonists. However, H2R and H3R antagonists significantly increased production of TNF-α and IL-1β, and decreased IL-10 levels. The H1R or H4R agonists stimulated the production of TNF-α and IL-1β, while the H2R or H3R agonists increased IL-10 release. Our results demonstrate that histamine induces microglia activation and the release of both proinflammatory and anti-inflammatory factors in rat brain, thus contributing to the development of inflammation in the brain. Graphical Abstract Histamine induces microglia activation and the release of both proinflammatory (TNF-α and IL-1β) and anti-inflammatory factors (IL-10) in rat brain, thus contributing to the development of inflammation in the brain.

The Effect of Histamine on Inward and Outward Currents in Mouse Retinal Amacrine Cells.

The expression of H1 receptor has been reported in amacrine cells of mouse and rat retinae. However, we assumed that other types of histamine receptors also function in amacrine cells. In order to confirm that histamine modulates the membrane potential in mouse amacrine cells, we measured voltage-gated currents using whole-cell configuration. Under voltage-clamp conditions, the amplitude of voltage-gated outward currents was enhanced by the application of 100µM histamine in 65% of amacrine cells. Histamine also increased the amplitudes of voltage-gated inward currents in 72% of amacrine cells. When antagonists of the histamine H1, H2, or H3 receptors were applied to histamine-sensitive amacrine cells, all three types of these inhibitors reduced the effect of histamine. Moreover, we classified recorded cells into seven types based on their morphological characteristics. Two of the seven types, diffuse multistratified cells and AII amacrine cells, responded significantly to histamine. These results indicate that histamine affected the membrane potential via three types of histamine receptors. Furthermore, there were differences in the responses to histamine among types of amacrine cells. Histamine may be one of the important neurotransmitters and/or neuromodulators in the visual processing.

Mast cells and histamine are triggering the NF-κB-mediated reactions of adult and aged perilymphatic mesenteric tissues to acute inflammation.

This study aimed to establish mechanistic links between the aging-associated changes in the functional status of mast cells and the altered responses of mesenteric tissue and mesenteric lymphatic vessels (MLVs) to acute inflammation. We used an in vivo model of acute peritoneal inflammation induced by lipopolysaccharide treatment of adult (9-month) and aged (24-month) F-344 rats. We analyzed contractility of isolated MLVs, mast cell activation, activation of nuclear factor-κB (NF-κB) without and with stabilization of mast cells by cromolyn or blockade of all types of histamine receptors and production of 27 major pro-inflammatory cytokines in adult and aged perilymphatic mesenteric tissues and blood. We found that the reactivity of aged contracting lymphatic vessels to LPS-induced acute inflammation was abolished and that activated mast cells trigger NF-κB signaling in the mesentery through release of histamine. The aging-associated basal activation of mesenteric mast cells limits acute inflammatory NF-κB activation in aged mesentery. We conclude that proper functioning of the mast cell/histamine/NF-κB axis is necessary for reactions of the lymphatic vessels to acute inflammatory stimuli as well as for interaction and trafficking of immune cells near and within the collecting lymphatics.

Localization of histamine (H1, H2, H3 and H4) receptors in mouse inner ear

Conclusion The present findings show that all four types of histamine receptors (H1R, H2R, H3R, and H4R) are present in the inner ear, thus supporting the hypothesis that histamine plays a physiological role in the inner ear. Objective To analyse the presence of histamine receptors in the normal mouse inner ear. Methods CBA/J mice were used in this study. The localization of H1R, H2R, H3R, and H4R in the inner ear, i.e. cochlea, vestibular end organs, vestibular ganglion, and endolymphatic sac, was studied by real-time PCR and immunohistochemistry. Results The mRNA for each receptor sub-type was detected in the inner ear. In the immunohistochemical study, the organ of Corti, spiral ganglion, vestibular ganglion, vestibular sensory epithelium, and endolymphatic sac cells showed an immunofluorescent reaction to all histamine receptors.

Antihistamine use in children

This review provides an overview of the use of antihistamines in children. We discuss types of histamine receptors and their mechanism of action, absorption, onset and duration of action of...

Roles of histamine on the expression of aldehyde dehydrogenase 1 in endometrioid adenocarcinoma cell line.

Cancer-initiating cells (CICs) are a limited number of cells that are essential for maintenance, recurrence, and metastasis of tumors. Aldehyde dehydrogenase 1 (ALDH1) has been recognized as a marker of CICs. We previously reported that ALDH1-high cases of uterine endometrioid adenocarcinoma showed poor prognosis, and that ALDH1 high population was more tumorigenic, invasive, and resistant to apoptosis than ALDH1 low population. Histamine plays a critical role in cancer cell proliferation, migration, and invasion. Here, we examined the effect of histamine on ALDH1 expression in endometrioid adenocarcinoma cell line. The addition of histamine increased ALDH1 high population, which was consistent with the result that histamine enhanced the invasive ability and the resistance to anticancer drug. Among 4 types of histamine receptors, histamine H1 and H2 receptor (H1R and H2R) were expressed in endometrioid adenocarcinoma cell line. The addition of H1R agonist but not H2R agonist increased ALDH1. The antagonist H1R but not H2R inhibited the effect of histamine on ALDH1 expression. These results indicated that histamine increased the expression of ALDH1 via H1R but not H2R. These findings may provide the evidence for exploring a new strategy to suppress CICs by inhibiting ALDH1 expression with histamine.

Functional characterization of histamine H4 receptor on human mast cells

Among the four different types of histamine receptors (H1-H4), H4R is predominantly expressed in immune cells and involved in immunomodulatory response. Here, in this study we determined the expression of H4R in human mast cells (HMC-1, LAD-2 and primary cord blood derived CD34+ human mast cells) and characterized its functional properties. Interestingly, we found that human mast cells responded to both histamine (natural ligand) and 4-methylhistamine (selective H4R agonist) for sustained intracellular calcium mobilization, degranulation and cytokine production. However, only histamine induced the release of cAMP, but 4-methylhistamine down regulates cAMP indicating that H4R mediates its effect through Gαi/o protein and H1R via Gαq protein. Furthermore, both histamine and 4-methylhistamine induced the production of cysteinyl leukotrienes and LTB4. Using human inflammation antibody array membrane, we found that H4R induced the expression of various inflammatory proteins, involving pro-inflammatory cytokines and chemokines and these are TGF-β1, TNF-α, TNF-β, PDGF-BB, TIMP-2, M-CSF, IP-10, IL-16, IL-6, IL-3, IL-10, MIP-1α, IL-1α, ICAM-1, Eotaxin-2, RANTES, IL-8, MCP-1, and IL-6sR. We also quantified the level of various inflammatory cytokines produced by human mast cells through H4R. It was observed that, the production level of Th2 cytokines IL-4(401.34pg/ml), IL-5 (64.21pg/ml) and IL-13 (1044pg/ml) and classical proinflammatory cytokines IL-6 (221.27pg/ml) and IL-1β (34.24pg/ml) and chemokines MCP-1(106pg/ml) and IL-8 (818.32pg/ml). Furthermore, activation of H4R caused the phosphorylation of ERK and PI3K in a time dependent manner. Taken together these data demonstrate that, the activation of H4R in human mast cells produced not only inflammatory mediators that are associated with allergic reactions but also other inflammatory conditions.

Histamine H4 Receptors and their Significance

The identification of the histamine H4 receptors has allowed new interest in the mechanism of action of an autacoid, which was originally identified in 1900s. Histamine is an important mediator of allergic disease, asthma and inflammation. The pharmacologic effects of histamine are mediated through four types of membrane histamine receptors, H1, H2, H3 and H4, which are all hepatohelical G-protein-coupled receptors. The H4 receptors, first considered to be present only on immunocompetent cells, are expressed on both the hematopoietic and non-hematopoietic cells. However, they are preferentially present on the cells, which are involved in the immune response, including eosinophils, basophils, mast cells, dendritic cells, helper T cells, cytolytic T cells and regulatory T cells. A number of other tissues including lung, heart, skin, small intestine and colon also express the H4 receptors. These receptors play a major role in the development of allergic diseases and asthma. The current understanding of allergic asthma is that it results from an abnormal TH2 production in response to environmental allergens, resulting in overproduction of IL-4, IL-5, and IL-13. The interaction of dendritic cells and allergen-specific T cells derives the polarization of naïve TH0 cells to the TH2 cells. Histamine along with other mediators plays a crucial role in this process. The H4 receptors have been identified as potential modulator for the activation of dendritic cells and polarization of T cells. In addition to their role in allergic asthma, these receptors are also involved in the inflammation of other tissues such as skin and the central nervous system. The vast body of evidence indicates a pro-inflammatory role for the H4 receptors, but there are reports where an antiinflammatory role for the H4 receptors, by their effects on regulatory T cells, has been reported. Agonist-biased signaling at the H4 receptors has added to the controversy regarding the role of these receptors. The histamine H1 receptor antagonists provide a limited relief in allergy and possess negligible to almost no efficacy in asthma. Consequently, the new histamine H4 receptor ligands may present an exciting opportunity to understand the etiology and pathogenesis of these disease states, along with new therapeutic opportunities.

Eicosanoids in exhaled air after non-specific challenge in patients with asthma

Introduction Histamine is a short-acting biogenic amine which plays an important role in allergic inflammation. Mast cells and basophiles store large quantities of histamine, which is released during degranulation in response to immunologic and nonimmunologic stimuli [1]. Histamine elicits many biological effects acting through four types of histamine receptors located on

Inhibition of Histamine H1 Receptor Activity Modulates Proinflammatory Cytokine Production of Dendritic Cells through c-Rel Activity

Background: Histamine exerts diverse effects on immune regulation through four types of histamine receptors (HRs). Among them, type 1 receptor (H1R) plays an important role in allergic inflammation. Dendritic cells (DCs), which express at least three types of HRs, are professional antigen-presenting cells controlling the development of allergic inflammation. However, the molecular mechanisms involved in H1R-mediated NF-ĸB signaling of DCs remain poorly defined. Methods: Bone-marrow (BM)-derived DCs (BM-DCs) were treated with H1R inverse agonists to interrupt basal H1R-mediated signaling. The crosstalk of H1R-mediated signaling and the NF-ĸB pathway was examined by NF-ĸB cellular activity using a luciferase reporter assay, NF-ĸB subunit analysis using Western blotting and TNF-α promoter activity using chromatin immunoprecipitation. Results: Blockage of H1R signaling by inverse agonists significantly inhibited TNF-α and IL-6 production of BM-DCs. H1R-specific agonists were able to enhance TNF-α production, but this overexpression was significantly inhibited by NF-ĸB inhibitor. The H1R inverse agonist ketotifen also suppressed cellular NF-ĸB activity, suggesting crosstalk between H1R and NF-ĸB signaling in DCs. After comprehensive analysis of NF-ĸB subunits, c-Rel protein expression was significantly down-regulated in ketotifen-treated BM-DCs, which led to inhibition of the promoter activity of TNF-α. Finally, adoptive transfer of the ketotifen-treated BM-DCs did not induce significant allergic airway inflammation compared to that of control cells in vivo. Conclusions: Our results suggest that c-Rel controls H1R-mediated proinflammatory cytokine production in DCs. This study provides a potential mechanism of H1R-mediated signaling and NF-ĸB pathway crosstalk in allergic inflammation.

Potential role of store-operated Ca2 + entry in Th2 response induced by histamine in human monocyte-derived dendritic cells

Store-operated calcium entry (SOCE) is the main Ca2+ influx pathway of dendritic cells (DCs). DCs primed with histamine facilitate Th2 immune response via different types of histamine receptors. Histamine induces DCs to release Ca2+ from internal store. Therefore, we wonder that whether histamine could activate SOCE in DCs through its receptors, and what's the functional relevance of the Ca2+ influx through SOCE induced by histamine in Th2 response. We certificate that histamine induced a transient Ca2+ release followed by pronounced Ca2+ influx after re-addition of external Ca2+ which could be inhibited by SOCE blockers SKF-96365 and BTP-2. Moreover, the percentages of DCs that showed an obvious Ca2+ release response to histamine were decreased in the presence of histamine 1 (H1) receptor antagonist pyridylethylamine (Pyr) or histamine 4 (H4) receptor antagonist JNJ7777120 (JNJ). Histamine up-regulated the mRNA expression of STIM1 in DCs, one of the two major proteins of SOCE channel. SOCE blocker BTP-2 and histamine receptor antagonists JNJ and Pyr inhibited the increase of CD86 induced by histamine on DCs. Histamine increased the level of IL-10 and decreased the level of IL-12p70 secreted by DCs. SOC blockers SKF and BTP-2 inhibited the level of both IL-10 and IL-12p70 secreted by DCs. Pretreatment of SOC blockers and H1, H4 receptor antagonists with DCs inhibited the Th2 polarization of T helper cells induced by histamine in mixed lymphocyte responses (MLR). We demonstrated that SOCE was involved in histamine-induced maturation and Th2 response of DCs which was through histamine 1 and 4 receptor.

Membrane-Initiated Estrogen Actions on Ion Channels and the Induction of Lordosis, the Rodent Female Sexual Behavior

The explosive increase of research in ”membrane-initiated” (also called ”non-genomic” or ”rapid” or ”acute”) estrogen actions in the past ten years not only established them as legitimate but also showed that they can activate many signaling pathways that can lead indirectly or even directly to the modulation of genomic functions. The latter raised the possibility that estrogens' membrane-initiated actions can synergize with their genomic actions. We have turned this possibility into a reality by first using cultured cells and then whole animals. With cultured neuroblastoma and MCF-7 breast cancer cells, we demonstrated that membrane-initiated estrogen actions could facilitate subthreshold doses of estradiol to accomplish a transcriptional facilitation, and found that the facilitation was mediated, at least in part, by pathways involving PKA and PKC. Using the estrogen-dependent rodent female sexual behavior, lordosis, as a study model, we found that implantation of a membrane-impermeable estrogen, which by itself could not induce the behavior, in the hypothalamic ventromedial nucleus (VMN) of female rats facilitated subthreshold estradiol similarly implanted later to induce lordosis. These findings, to our knowledge, comprise the first demonstration of the synergism between estrogen's membraneinitiated and genomic actions. Consistent with our cell culture studies, the facilitation of lordosis induction also required functioning PKA and PKC. Several lines of evidence indicated that an increase in neuronal activity during the initial stage of estrogen administration is required for the induction of lordosis. Therefore, whether the activity of VMN neurons is modulated by the membrane-initiated actions of the estrogen applied to the hypothalamus was investigated. With extracellular single-neuron recording of VMN cells in hypothalamic slices of female rats, it was found that acutely applied estradiol (acute E2) could i) potentiate the excitation mediated by two distinct types of receptors, G protein-coupled excitatory histamine (HA) receptors and NMDA ion channel/receptors, and ii) attenuate inhibition caused by G protein-coupled inhibitory HA receptors. These findings raised the possibility that acute E2 can potentially working through three independent mechanisms to modulate these responses. This possibility was evaluated using whole cell patch clamp studies. Corresponding to extracellular recording findings, HA could evoke de- and/or hyper-polarization, and NMDA could evoke only depolarization. Acute application of E2 could, again, potentiate HA and NMDA depolarization and attenuate HA hyperpolarization. To search for mechanisms, pharmacological analyses of HA responses were performed to define receptors responsible for excitation and inhibition, and effects of acute E2 on individual types of HA receptors were studied. Results from these studies, together with current knowledge about HA receptors, point to a likely mechanism underlying non-genomic estrogen modulations of HA responses: acute E2 inhibits K(superscript +) channels through the facilitation of G(subscript q/11) coupled to histaminergic H1 receptors, to potentiate HA depolarization/ excitation as well as to attenuate hyperpolarization/inhibition. We also searched for mechanism(s) underlying acute E2 potentiation of NMDA depolarization/excitation by characterizing NMDA actions. We found that both NMDA and acute E2 could reduce afterhyperpolarizations, which are mediated by Ca(superscript ++)-activated K(superscript +) channels. Therefore, attenuation of these channels appears to be one way acute E2 can potentiate NMDA depolarization/excitation. Thus, in the induction of lordosis at least, membraneinitiated non-genomic estrogen actions appear to facilitate genomic actions by both activating signaling pathways involving PKA and PKC and by inhibiting certain K(superscript +) channels.