Дисциплина Экспериментальная патобиохимия клетки
Нейротрансмиттеры
| Mediator | Receptors | Sources, Receptors Expressed by | Comments |
|---|---|---|---|
| Acetylcholine | Nicotinergic (nAChR) and muscarinergic (mAchR) acetylcholine receptors | Autonomic cholinergic nerves, keratinocytes, lymphocytes, melanocytes | Mediates itch in atopic dermatitis patients. mAChR3 is probably involved in itch. |
| Regulates keratinocyte proliferation, adhesion, migration, and differentiation. | |||
| Inhibits NFκB transcription; inhibits release of TNF-α, IL-1β. | |||
| Adenosine triphosphate (ATP) | Purinergic P2 receptors (seven ionotropic P2XRs or eight metabotropic P2YRs). HMEC-1 express P2X4, P2X5, P2X7, P2Y2, and P2Y11 receptors, and weakly P2X1 and P2X3 | Involved in pain transmission and neurogenic inflammation. Induces release of IL-6, IL-8, MCP-1, Gro-α from HMEC-1 cells. Increases expression of ICAM-1 in HMEC-1. Increases leukocyte recruitment and adhesion to EC. | |
| Calcitonin gene-related peptide (CGRP) (and adrenomedullin, ADM) | CGRP receptor = calcitonin-like receptor/receptor activity modifying protein 1 (CL-R/RAMP1) | CGRP: sensory nerve fibers | Pain transmission (central but not periphery), prolongation of itch latency following SP injection (inhibitory effect on itching). |
| ADM-receptor = CL-R/RAMP2 or CL-R/RAMP3 | CGRP receptor: keratinocytes | Sensitization of sensory nerve endings. Increase of CGRP fibers in itchy skin diseases. CGRP stimulates adhesion of leukocytes and monocytes to endothelial cells. Vasodilatation and relaxation of arterioles; CGRP but not ADM potentiates edema in venules, ADM less potent than CGRP as a direct vasodilator. ADM but not CGRP potentiates neutrophil accumulation induced by IL-1β. CGRP stimulates TNF-α release from mast cells. Potential role on angiogenesis and keratinocyte migration. With adrenomedullin, CGRP inhibits progression of sepsis. | |
| Catecholamines | Adrenergic receptors (AR): α1a, α1b, α2A, α2B, α2C, α2D, β1, β2 and β3 AR | Released by nerve fibers, keratinocytes, melanocytes. | Suppresses IL-12 production and increases IL-10 release in DCs. Inactivates NFκB. Augments T-cell production. Inhibits TNF-α release from monocytes. Modulates keratinocyte differentiation. Regulates melanogenesis. |
| Receptors by natural killer cells, monocytes, T cells Inducible by T cells, B cells | |||
| Corticotropin releasing hormone (CRH) (see also opioids and proopiomelanocortin) | CRH-R1 and -R2 | CRH-R1: keratinocytes, mast cells | Release of histamine, cytokines, TNF-α, VEGF from mast cells. CRH-like immunoreactivity on sensory nerves (rat). CRH-R1 downregulation upon stress and infection. CRH-R2 mRNA induced by IL-4 in mast cells. High expression of CRH-R1 in urticaria and lichen simplex. CRH proliferative in fibroblasts and antiproliferative in keratinocytes. Stimulates corticosterone production in fibroblasts. Downregulates IL-18 in human keratinocytes. CRH regulates pigmentation, produces analgesia in thermal pain models. |
| CRH-R2: bone marrow mast cells | |||
| Endocannabinoids | Cannabinoid receptors (CB1, CB2) | Released by nerves, T cells, macrophages | Antipruritic in the periphery; antinociceptive and antihyperalgesic in rats and humans. Activate the TRPV1 pathway, inhibit cytokines during innate and adaptive immune responses, downregulate release of IL-1, TNF-α and CXCL8. |
| Receptors on nerves, mast cells, macrophages, keratinocytes, skin appendages | Suppress TH1-cell activity and increase TH2-cell activity; decreases production of IFN-γ and IL-12 and expression of IL-12R; increases IL-4 production. | ||
| LPS stimulates release of cannabinoids from macrophages and DCs; macrophages increase production of endocannabinoids in response to LPS; protective effect during endotoxemia and sepsis. | |||
| Attracts human eosinophils, B cells, DCs, increased in HIV. | |||
| CB2 reduces cutaneous edema; CB1-dependent reduction of transglutaminase, PKC, and AP-1 in keratinocytes; CB2-dependent release of β-endorphin from keratinocytes. | |||
| Anti-inflammatory and antipruritic in the periphery, downregulates IL-1 and TNF-α, and upregulates IL-10. | |||
| Endothelin (ET) | Endothelin receptors (ETA, ETB) | Nerves, endothelium, mast cells, fibroblasts, melanocytes | Burning itch. Degraded by chymase via ETA, receptor activation thereby regulating inflammation and probably itch. ET-1 induced TNF-α, and IL-6 production by mast cells. Tissue remodeling and fibrogenesis by inducing synthesis of collagen I. ETB mediates upregulation of melanoma cell adhesion molecule. |
| Interleukin-31 | IL-31R (heterodimer) | Keratinocytes, sensory nerves | IL-31 released during skin inflammation by T cells and macrophages, induce release of inflammatory mediators from keratinocytes, induces itching. |
| Kallikreins, proteases | Partly by proteinase-activated receptors (PARs, tryptic enzymes) | PAR1: keratinocytes, endothelial cells, mast cells, platelets | Tryptase attenuates the vasodilator activity of calcitonin gene-related peptide. Chymase induced angiogenesis, clearance of cytokines. |
| PAR2: keratinocytes, endothelial cells, mast cells, nerves | Microbial agents induce prekallikrein synthesis; hK5 and hK7 are inhibited by LEKT1. | ||
| PAR4: T cells, mast cells, (macrophages?) | pH affects serine protease activity in the epidermis. Kallikreins may be involved in systemic sclerosis. | ||
| PAR1: platetet regulation; induces proliferation in keratinocytes; MMP-1 activates PAR1. | |||
| PAR2: massive itch behavior in mice overexpressing epidermal kallikrein-7. Potential role of other kallikreins. Chymase degrades pruritic and antipruritic peptides. Tryptase induces inflammation and itch by a neurogenic mechanism via PAR2. Microbial proteases may induce itch and inflammation via PAR2 PAR4? | |||
| Kinins | Bradykinin receptors (B1, B2) | Endothelial cells, immunocytes, keratinocytes, sensory nerves fibers | Bradykinin induces pain over pruritus. Modulates nociception. B2 receptor antagonists reduce itch. Bradykinin induces MAP kinase phosphorylation in keratinocytes. |
| Leukotriene B4 | Leukotriene B4 receptor | Sensory nerves fibers, keratinocytes | Leukotriene B4 induces itch and is also involved in the substance P- and nociceptin-mediated induction of itch. Mast cell-derived LTB4 modulates T-cell proliferation and activation. |
| Neurokinin A (NKA) | Tachykinin (neurokinin) receptor-1, −2, −3 | Sensory nerve fibers, dermal microvascular endothelial cells, keratinocytes, B cells | SP: upregulation ICAM-1 and VCAM-1, priming of mast cells. Release of TNF-α, histamine, leukotriene B4, and prostaglandins from mast cells (agents involved in pruritus and burning). SP involved in central pain transmission. |
| Substance P (SP) | Protachykinin contributes to delta-opioid receptor-mediated pain processing. | ||
| Hemokinin-1 (HK-1) | HK-1: expressed by T cells and macrophages; involved in B-cell development and stimulates IFN-γ production in T cells. | ||
| NKA: upregulation of keratinocyte nerve growth factor expression. | |||
| Endovanilloids (heat, acidosis, eicosanoids, histamine, bradykinin, extracellular ATP, prostaglandins, various neurotrophins) | Activation of vanilloid receptor-1 (TRPV1) | TRPV1 is expressed on sensory neurons, mast cells, epidermal and hair follicle keratinocytes, Langerhans cells, smooth muscle, sebocytes | TRPV1: short-term TRPV1 activation: pain and itch induction, depletes neuropeptides from sensory neurons. Long-term antipruritic effect of TRPV1 agonists (e.g., capsaicin): suspend interplay between sensory neurons and mast cells. Affects epidermal and hair follicle proliferation, differentiation, apoptosis, and cytokine release. Increased expression in epidermal keratinocytes of prurigo nodularis patients; induces neurogenic inflammation, sensitized by PAR2. |
| Sensitization of TRPV1 via activation of specific receptors | TRPV2: expressed by medium- to large-diameter sensory neurons, induced by noxious heat; upregulation contributes to peripheral sensitization during inflammation and is responsible for pain hypersensitivity to noxious high-temperature stimuli. | ||
| TRPV3: induced by innocuous (warm) temperatures, expressed by keratinocytes. Impaired thermosensation in mice lacking TRPV3; interaction with P2X receptors? | |||
| TRPV4: activated by heat (25°C), by cell swelling, and PLA2; expressed by sensory neurons, sympathetic nerves, sweat glands, keratinocytes, hair cells, Merkel cells, murine aorta endothelial cells; involved in pain-related behavior; transduction of osmotic and mechanical stimuli. | |||
| TRPM8: activated by temperature (below 27°C), menthol, eucalyptol; expressed by small-diameter DRGs; no colocalization with neuropeptides. | |||
| TRPA1: activated at 17°C, expressed exclusively in DRGs, sensitive to icilin (AG-3-5), insensitive to menthol, eucalyptol; colocalizes with TRPV1, SP, and CGRP. | |||
| Galanin | Galanin receptor (1–3) (GalR1–3) | Gal: nerve terminals and fibers of the dermis and basal layer of epidermis | Mice overexpressing galanin show moderate heat hypoalgesia, reduced spinal sensitization, and reduced development of neuropathic painlike behavior. Increases membrane excitability and enhances Ca2+ currents in acutely dissociated rat DRGs. |
| GalR: nerves fibers | |||
| Histamine | Histamine receptors (H1R, H4R) | Sensory nerve fibers, endothelial cells, T cells | In humans, histamine induces itch by stimulating specific sensory fibers, whereas H1 and and H2 antagonists reduce itch in numerous clinical trials. In mice, H3 antagonists induce scratching behavior, whereas H1 and H4 antagonists effectively suppress pruritus. |
| Induces also plasma extravasation and vasodilatation; communicates with T cells via histamine receptors. | |||
| Nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophins (NT-3, NT-4) | Specific receptors trk A: NGF; trk B: NT-4, BDNF; Trk C: NT-3 | Keratinocytes, mast cells, fibroblasts, eosinophils | NGF levels enhanced in atopic dermatitis (AD). |
| Induces tryptase release from mast cells. | |||
| Inducible by histamine. trk A: enhanced in keratinocytes during inflammation. NT-4: enhanced in AD and induces sprouting. | |||
| BDNF: increases eosinophil chemotaxis levels in AD and inhibits apoptosis. Neurotrophins sensitize receptive nerve endings and upregulate neuronal neuropeptides and TRPV1. | |||
| NGF is upregulated during inflammation, stimulates mast cells and released by them. | |||
| NGF increases number of mast cells, induces proliferation and differentiation of B cells, and stimulates neuronal cells. | |||
| NT-3 inhibits inflammatory hyperalgesia in rats. | |||
| During inflammation, upregulated BDNF accelerates tactile recovery in rats. | |||
| Neuropeptide Y (NPY) | Neuropeptide Y receptor-1 and -2 (Y1, Y2) | Sensory nerves, keratinocytes | Inhibition of adenylyl cyclase, regulating blood flow, reflex vasoconstriction. |
| Opioids | μ-, κ-, δ-Opioid receptors (partly receptor-independent cell activation) | Sensory nerves, keratinocytes, T cells, B cells | Antipruritic effect of μ-opioid antagonists (central effect) and κ-opioid agonists (spinal cord level). Opioid agonists do not provoke itch upon injection or intradermal application. μ-Opioid receptor upregulation in atopic dermatitis. |
| Keratinocyte-derived β-endorphin induces peripheral analgesia. T cells express various opioid receptors: opioids induce T-cell chemotaxis. Inhibits B-cell IgG production via IL-6 modulation. Absence of classical opioid receptors on human mononuclear cells. | |||
| Pituitary adenylate cyclase activating polypeptide (PACAP) | PAC1R, PAC2R, PAC3R (and splice variants); also binds to VPAC1R and VPAC2R | Sensory and autonomic nerves, T cells, macrophages, keratinocytes, dermal microvascular endothelial cells, Merkel cells | In vivo: potent vasodilatator; involved in flush, pain, neurodegeneration. PACAP enhanced in lesions of psoriasis patients. Enhances animal survival during sepsis. |
| Downregulates capacity of APCs for antigen presentation: inhibiting the induction of contact hypersensitivity by reducing murine LCs. | |||
| In vitro: induces release of histamine from mast cells; downregulates release of IL-2, IL-6, TNF-α from T cells and macrophages. Early inflammation: drives T cells into an anti-inflammatory response. Late inflammation: stimulates T-cell proliferation and differentiation into Th2 helper cells. | |||
| Proopimelanocortins (POMC gene) (endorphins, enkephalins, dynorphins, MSH, ACTH, β-lipotrophin) (see also CRH, opioids) | Opioid receptors, MC-R, ACTH-R, CRH-R | Melanocytes, keratinocytes, adnexal epithelial cells, endothelial cells, Langerhans cells, mast cells, fibroblasts, monocytes, and macrophages | Upon cleavage by prohormone convertase (PC1, 2) POMC-derived peptides mediate a variety of processes in skin function (please refer to the specific section of POMC peptides). |
| Prostaglandins | Prostanoid (P) receptors (DP, EP, IP) | Sensory nerve fibers, keratinocytes | PGE2 induces pain over itch in humans but not mice. PGD2 reduces IgE-mediated scratching in mice. PGE2 is a vasodilator and may potentiate edema in the skin; DP1 impedes TNF-α-induced migration of human LCs, inhibits the chemotactic responses of human LCs to chemokines, induces IL-10 production. |
| Mice lacking DP2 and EP2 show reduced flushing in mice. | |||
| PGE2 and PGI2 upregulate ICAM-1 expression in human gingival fibroblasts; COX-2 inhibitor (NS-398) elevates IgE and a systemic TH2 response to antigen in mice. | |||
| Somatostatin (SST) (1–14, 1–28) | sst receptors 1–5 | Skin: Merkel cells, sweat glands, Langerhans cells, keratinocytes, fibroblasts, macrophages | In atopic skin, the expression of SST diasappeared. SST has inhibitory effects on T-cell proliferation. SST-2 is found macrophages in sarcoidosis. |
| Antiproliferative on keratinocytes. Anti-inflammatory: downregulation of proinflammatory cytokines. Sst receptors upregulated in melanoma. | |||
| Secretoneurin | Not known | Sensory nerve fibers | Secretoneurin triggers monocyte migration, modulates neutrophil activity, and stimulates endothelial migration. |
| Vasoactive intestinal polypeptide (VIP) | VPAC1R, VPAC2R | Sensory and autonomic nerves, T cells, macrophages, keratinocytes, dermal microvascular endothelial cells, Merkel cells, smooth muscle cells | Anti-inflammatory in mammals and humans; induces NO synthesis; upregulates IL-10 in DCs; downregulates TLR4 expression and TLR4-mediated chemokine generation; downregulates IL-1, TNF-α, and MCP-1; antiapoptotic in Th2 cells; induces vasodilatation; supports migration of keratinocytes; regulation of blood vessel function. |
| Inhibits delayed-type hypersensitivity and prevents from graft-versus-host disease in vivo. | |||
| Enhances outcome of animal survival during sepsis. Induces pruritus and increases blood flow in human skin. Poor effect on plasma extravasation. |
Последнее изменение: Среда, 4 Май 2016, 21:45