Abstract
Oxytocin (OT), a hypothalamic neuropeptide involved in regulating the social behaviour of all vertebrates, has been proposed as a treatment for a number of neuropsychiatric disorders characterised by deficits in the social domain. Over the last few decades, advances focused on understanding the social effects of OT and its role in physiological conditions and brain diseases, but much less has been done to clarify the molecular cascade of events involved in mediating such effects and in particular the cellular and molecular pharmacology of OT and its target receptor (OTR) in neuronal and glial cells.
The entity and persistence of OT activity in the brain is closely related to the expression and regulation of the OTR expressed on the cell surface, which transmits the signal intracellularly and permits OT to affect cell function. Understanding the various signalling mechanisms mediating OTR-induced cell responses is crucial to determine the different responses in different cells and brain regions, and the success of OT and OT-derived analogues in the treatment of neurodevelopmental and psychiatric diseases depends on how well we can control such responses. In this review, we will consider the most important aspects of OT/OTR signalling by focusing on the molecular events involved in OT binding and coupling, on the main signalling pathways activated by the OTR in neuronal cells and on intracellular and plasma membrane OTR trafficking, all of which contribute to the quantitative and qualitative features of OT responses in the brain.
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References
Ahn S, Nelson CD, Garrison TR et al (2003) Desensitization, internalization, and signaling functions of beta-arrestins demonstrated by RNA interference. Proc Natl Acad Sci U S A 100(4):1740–1744. doi:10.1073/pnas.262789099
Alberi S, Dreifuss JJ, Raggenbass M (1997) The oxytocin-induced inward current in vagal neurons of the rat is mediated by G protein activation but not by an increase in the intracellular calcium concentration. Eur J Neurosci 9(12):2605–2612
Albizu L, Cottet M, Kralikova M et al (2010) Time-resolved FRET between GPCR ligands reveals oligomers in native tissues. Nat Chem Biol 6(8):587–594. doi:10.1038/nchembio.396
Antoni FA, Chadio SE (1989) Essential role of magnesium in oxytocin-receptor affinity and ligand specificity. Biochem J 257(2):611–614
Bathgate-Siryk A, Dabul S, Pandya K et al (2014) Negative impact of β-arrestin-1 on post-myocardial infarction heart failure via cardiac and adrenal-dependent neurohormonal mechanisms. Hypertension 63(2):404–412. doi:10.1161/HYPERTENSIONAHA.113.02043
Ben-Ari Y, Cherubini E, Corradetti R et al (1989) Giant synaptic potentials in immature rat CA3 hippocampal neurones. J Physiol 416:303–325
Berrada K, Plesnicher CL, Luo X et al (2000) Dynamic interaction of human vasopressin/oxytocin receptor subtypes with G protein-coupled receptor kinases and protein kinase C after agonist stimulation. J Biol Chem 275(35):27229–27237. doi:10.1074/jbc.M002288200
Berry-Kravis E, Levin R, Shah H et al (2015) Cholesterol levels in fragile X syndrome. Am J Med Genet A 167A(2):379–384. doi:10.1002/ajmg.a.36850
Blume A, Bosch OJ, Miklos S et al (2008) Oxytocin reduces anxiety via ERK1/2 activation: local effect within the rat hypothalamic paraventricular nucleus. Eur J Neurosci 27(8):1947–1956. doi:10.1111/j.1460-9568.2008.06184.x
Brann MR, Collins RM, Spiegel A (1987) Localization of mRNAs encoding the alpha-subunits of signal-transducing G-proteins within rat brain and among peripheral tissues. FEBS Lett 222(1):191–198
Bredt DS, Snyder SH (1992) Nitric oxide, a novel neuronal messenger. Neuron 8(1):3–11
Brighton PJ, Rana S, Challiss RJ et al (2011) Arrestins differentially regulate histamine- and oxytocin-evoked phospholipase C and mitogen-activated protein kinase signalling in myometrial cells. Br J Pharmacol 162(7):1603–1617. doi:10.1111/j.1476-5381.2010.01173.x
Burger K, Gimpl G, Fahrenholz F (2000) Regulation of receptor function by cholesterol. Cell Mol Life Sci 57(11):1577–1592
Busnelli M, Sauliere A, Manning M et al (2012) Functional selective oxytocin-derived agonists discriminate between individual G protein family subtypes. J Biol Chem 287(6):3617–3629. doi:10.1074/jbc.M111.277178
Busnelli M, Bulgheroni E, Manning M et al (2013a) Selective and potent agonists and antagonists for investigating the role of mouse oxytocin receptors. J Pharmacol Exp Ther 346(2):318–327. doi:10.1124/jpet.113.202994
Busnelli M, Mauri M, Parenti M et al (2013b) Analysis of GPCR dimerization using acceptor photobleaching resonance energy transfer techniques. Methods Enzymol 521:311–327. doi:10.1016/B978-0-12-391862-8.00017-X
Busnelli M, Kleinau G, Muttenthaler M et al (2016) Design and characterization of Superpotent bivalent ligands targeting oxytocin receptor dimers via a channel-like structure. J Med Chem 59(15):7152–7166. doi:10.1021/acs.jmedchem.6b00564
Cattaneo MG, Chini B, Vicentini LM (2008) Oxytocin stimulates migration and invasion in human endothelial cells. Br J Pharmacol 153(4):728–736. doi:10.1038/sj.bjp.0707609
Chaviaras S, Mak P, Ralph D et al (2010) Assessing the antidepressant-like effects of carbetocin, an oxytocin agonist, using a modification of the forced swimming test. Psychopharmacology (Berl) 210(1):35–43. doi:10.1007/s00213-010-1815-x
Chini B, Manning M (2007) Agonist selectivity in the oxytocin/vasopressin receptor family: new insights and challenges. Biochem Soc Trans 35(Pt 4):737–741. doi:10.1042/BST0350737
Chini B, Mouillac B, Ala Y et al (1995) Tyr115 is the key residue for determining agonist selectivity in the V1a vasopressin receptor. EMBO J 14(10):2176–2182
Chini B, Manning M, Guillon G (2008) Affinity and efficacy of selective agonists and antagonists for vasopressin and oxytocin receptors: an “easy guide” to receptor pharmacology. Prog Brain Res 170:513–517. doi:10.1016/S0079-6123(08)00438-X
Conti F, Sertic S, Reversi A et al (2009) Intracellular trafficking of the human oxytocin receptor: evidence of receptor recycling via a Rab4/Rab5 “short cycle”. Am J Physiol Endocrinol Metab 296(3):E532–E542. doi:10.1152/ajpendo.90590.2008
Cottet M, Albizu L, Perkovska S et al (2010) Past, present and future of vasopressin and oxytocin receptor oligomers, prototypical GPCR models to study dimerization processes. Curr Opin Pharmacol 10(1):59–66. doi:10.1016/j.coph.2009.10.003
De la Mora MP, Pérez-Carrera D, Crespo-Ramírez M, Tarakanov A, Fuxe K, Borroto-Escuela DO (2016) Signaling in dopamine D2 receptor-oxytocin receptor heterocomplexes and its relevance for the anxiolytic effects of dopamine and oxytocin interactions in the amygdala of the rat. Biochim Biophys Acta 1862(11):2075–2085. doi:10.1016/j.bbadis.2016.07.004
Devost D, Zingg HH (2003) Identification of dimeric and oligomeric complexes of the human oxytocin receptor by co-immunoprecipitation and bioluminescence resonance energy transfer. J Mol Endocrinol 31(3):461–471
Devost D, Girotti M, Carrier ME et al (2005) Oxytocin induces dephosphorylation of eukaryotic elongation factor 2 in human myometrial cells. Endocrinology 146(5):2265–2270. doi:10.1210/en.2004-1428
Devost D, Wrzal P, Zingg HH (2008) Oxytocin receptor signalling. Prog Brain Res 170:167–176. doi:10.1016/S0079-6123(08)00415-9
Eftekhari S, Shahrokhi A, Tsintsadze V et al (2014) Response to comment on “oxytocin-mediated GABA inhibition during delivery attenuates autism pathogenesis in rodent offspring”. Science 346(6206):176. doi:10.1126/science.1256009
Eliava M, Melchior M, Knobloch-Bollmann HS et al (2016) A new population of parvocellular oxytocin neurons controlling magnocellular neuron activity and inflammatory pain processing. Neuron 89(6):1291–1304. doi:10.1016/j.neuron.2016.01.041
Fanelli F, Barbier P, Zanchetta D et al (1999) Activation mechanism of human oxytocin receptor: a combined study of experimental and computer-simulated mutagenesis. Mol Pharmacol 56(1):214–225
Favre N, Fanelli F, Missotten M et al (2005) The DRY motif as a molecular switch of the human oxytocin receptor. Biochemistry 44(30):9990–10008. doi:10.1021/bi0509853
Feifel D, Shilling PD, MacDonald K (2016) A review of oxytocin’s effects on the positive, negative, and cognitive domains of schizophrenia. Biol Psychiatry 79(3):222–233. doi:10.1016/j.biopsych.2015.07.025
Ferguson JN, Young LJ, Hearn EF et al (2000) Social amnesia in mice lacking the oxytocin gene. Nat Genet 25(3):284–288. doi:10.1038/77040
Fernando RN, Larm J, Albiston AL et al (2005) Distribution and cellular localization of insulin-regulated aminopeptidase in the rat central nervous system. J Comp Neurol 487(4):372–390. doi:10.1002/cne.20585
Francis SM, Kistner-Griffin E, Yan Z et al (2016) Variants in adjacent oxytocin/vasopressin gene region and associations with ASD diagnosis and other autism related endophenotypes. Front Neurosci 10:195. doi:10.3389/fnins.2016.00195
Frantz MC, Rodrigo J, Boudier L et al (2010) Subtlety of the structure-affinity and structure-efficacy relationships around a nonpeptide oxytocin receptor agonist. J Med Chem 53(4):1546–1562. doi:10.1021/jm901084f
Garibay JL, Kozasa T, Itoh H et al (1991) Analysis by mRNA levels of the expression of six G protein alpha-subunit genes in mammalian cells and tissues. Biochim Biophys Acta 1094(2):193–199
Gimpl G, Fahrenholz F (2002) Cholesterol as stabilizer of the oxytocin receptor. Biochim Biophys Acta 1564(2):384–392
Gimpl G, Klein U, Reilander H et al (1995) Expression of the human oxytocin receptor in baculovirus-infected insect cells: high-affinity binding is induced by a cholesterol-cyclodextrin complex. Biochemistry 34(42):13794–13801
Gimpl G, Burger K, Politowska E et al (2000) Oxytocin receptors and cholesterol: interaction and regulation. Exp Physiol 85:41S–49S
Gimpl G (2016) Interaction of G protein coupled receptors and cholesterol. Chem Phys Lipids 199:61–73. doi:10.1016/j.chemphyslip.2016.04.006
Gong L, Gao F, Li J et al (2015) Oxytocin-induced membrane hyperpolarization in pain-sensitive dorsal root ganglia neurons mediated by Ca(2+)/nNOS/NO/KATP pathway. Neuroscience 289:417–428. doi:10.1016/j.neuroscience.2014.12.058
Gravati M, Busnelli M, Bulgheroni E et al (2010) Dual modulation of inward rectifier potassium currents in olfactory neuronal cells by promiscuous G protein coupling of the oxytocin receptor. J Neurochem 114(5):1424–1435. doi:10.1111/j.1471-4159.2010.06861.x
Grinevich V, Knobloch-Bollmann HS, Eliava M et al (2016) Assembling the puzzle: pathways of oxytocin signaling in the brain. Biol Psychiatry 79(3):155–164. doi:10.1016/j.biopsych.2015.04.013
Grotegut CA, Mao L, Pierce SL et al (2016) Enhanced uterine contractility and stillbirth in mice lacking G protein-coupled receptor kinase 6 (GRK6): implications for oxytocin receptor desensitization. Mol Endocrinol 30(4):455–468. doi:10.1210/me.2015-1147
Guastella AJ, Hickie IB (2016) Oxytocin treatment, circuitry, and autism: a critical review of the literature placing oxytocin into the autism context. Biol Psychiatry 79(3):234–242. doi:10.1016/j.biopsych.2015.06.028
Guzzi F, Zanchetta D, Cassoni P et al (2002) Localization of the human oxytocin receptor in caveolin-1 enriched domains turns the receptor-mediated inhibition of cell growth into a proliferative response. Oncogene 21(11):1658–1667. doi:10.1038/sj.onc.1205219
Hasbi A, Devost D, Laporte SA et al (2004) Real-time detection of interactions between the human oxytocin receptor and G protein-coupled receptor kinase-2. Mol Endocrinol 18(5):1277–1286. doi:10.1210/me.2003-0440
Heise C, Taha E, Murru L et al (2016) eEF2K/eEF2 pathway controls the excitation/inhibition balance and susceptibility to epileptic seizures. Cereb Cortex. doi:10.1093/cercor/bhw075
Hoare S, Copland JA, Strakova Z et al (1999) The proximal portion of the COOH terminus of the oxytocin receptor is required for coupling to g(q), but not g(i). Independent mechanisms for elevating intracellular calcium concentrations from intracellular stores. J Biol Chem 274(40):28682–28689
Huang H, Michetti C, Busnelli M et al (2014) Chronic and acute intranasal oxytocin produce divergent social effects in mice. Neuropsychopharmacology 39(5):1102–1114. doi:10.1038/npp.2013.310
Inoue T, Kimura T, Azuma C et al (1994) Structural organization of the human oxytocin receptor gene. J Biol Chem 269(51):32451–32456
Insel TR, Winslow JT, Witt DM (1992) Homologous regulation of brain oxytocin receptors. Endocrinology 130(5):2602–2608. doi:10.1210/endo.130.5.1315251
Jiang M, Bajpayee NS (2009) Molecular mechanisms of go signaling. Neurosignals 17(1):23–41. doi:10.1159/000186688
Jurek B, Slattery DA, Maloumby R et al (2012) Differential contribution of hypothalamic MAPK activity to anxiety-like behaviour in virgin and lactating rats. PLoS One 7(5):e37060. doi:10.1371/journal.pone.0037060
Kamato D, Thach L, Bernard R et al (2015) Structure, function, pharmacology, and therapeutic potential of the G protein, Galpha/q,11. Front Cardiovasc Med 2:14. doi:10.3389/fcvm.2015.00014
Kim J, Stirling KJ, Cooper ME et al (2013) Sequence variants in oxytocin pathway genes and preterm birth: a candidate gene association study. BMC Med Genet 14:77. doi:10.1186/1471-2350-14-77
Kim SH, MacIntyre DA, Hanyaloglu AC et al (2016) The oxytocin receptor antagonist, atosiban, activates pro-inflammatory pathways in human amnion via G(alphai) signalling. Mol Cell Endocrinol 420:11–23. doi:10.1016/j.mce.2015.11.012
Kimura T, Tanizawa O, Mori K et al (1992) Structure and expression of a human oxytocin receptor. Nature 356(6369):526–529. doi:10.1038/356526a0
King LB, Walum H, Inoue K et al (2016) Variation in the oxytocin receptor gene predicts brain region-specific expression and social attachment. Biol Psychiatry 80(2):160–169. doi:10.1016/j.biopsych.2015.12.008
Klein U, Gimpl G, Fahrenholz F (1995) Alteration of the myometrial plasma membrane cholesterol content with beta-cyclodextrin modulates the binding affinity of the oxytocin receptor. Biochemistry 34(42):13784–13793
Knobloch HS, Charlet A, Hoffmann LC et al (2012) Evoked axonal oxytocin release in the central amygdala attenuates fear response. Neuron 73(3):553–566. doi:10.1016/j.neuron.2011.11.030
Kow LM, Johnson AE, Ogawa S et al (1991) Electrophysiological actions of oxytocin on hypothalamic neurons in vitro: neuropharmacological characterization and effects of ovarian steroids. Neuroendocrinology 54(5):526–535
Ku CY, Qian A, Wen Y et al (1995) Oxytocin stimulates myometrial guanosine triphosphatase and phospholipase-C activities via coupling to G alpha q/11. Endocrinology 136(4):1509–1515. doi:10.1210/endo.136.4.7895660
Landgraf R, Neumann ID (2004) Vasopressin and oxytocin release within the brain: a dynamic concept of multiple and variable modes of neuropeptide communication. Front Neuroendocrinol 25(3–4):150–176. doi:10.1016/j.yfrne.2004.05.001
Lee SM, Booe JM, Pioszak AA (2015) Structural insights into ligand recognition and selectivity for classes A, B, and C GPCRs. Eur J Pharmacol 763(Pt B):196–205. doi:10.1016/j.ejphar.2015.05.013
Leng G, Ludwig M (2008) Neurotransmitters and peptides: whispered secrets and public announcements. J Physiol 586(23):5625–5632. doi:10.1113/jphysiol.2008.159103
Leonzino M, Busnelli M, Antonucci F et al (2016) The timing of the excitatory-to-inhibitory GABA switch is regulated by the oxytocin receptor via KCC2. Cell Rep 15(1):96–103. doi:10.1016/j.celrep.2016.03.013
Lin YT, Huang CC, Hsu KS (2012) Oxytocin promotes long-term potentiation by enhancing epidermal growth factor receptor-mediated local translation of protein kinase Mzeta. J Neurosci 32(44):15476–15488. doi:10.1523/JNEUROSCI.2429-12.2012
Lingwood D, Simons K (2010) Lipid rafts as a membrane-organizing principle. Science 327(5961):46–50. doi:10.1126/science.1174621
Liu D, Seuthe AB, Ehrler OT et al (2005) Oxytocin-receptor binding: why divalent metals are essential. J Am Chem Soc 127(7):2024–2025. doi:10.1021/ja046042v
Liu X, Kawashima M, Miyagawa T et al (2015) Novel rare variations of the oxytocin receptor (OXTR) gene in autism spectrum disorder individuals. Hum Genome Var 2:15024. doi:10.1038/hgv.2015.24
Lohse MJ, Hoffmann C (2014) Arrestin interactions with G protein-coupled receptors. Handb Exp Pharmacol 219:15–56. doi:10.1007/978-3-642-41199-1_2
Ludwig M, Leng G (2006) Dendritic peptide release and peptide-dependent behaviours. Nat Rev Neurosci 7(2):126–136. doi:10.1038/nrn1845
Ludwig M, Stern J (2015) Multiple signalling modalities mediated by dendritic exocytosis of oxytocin and vasopressin. Philos Trans R Soc Lond B Biol Sci 370(1672). doi:10.1098/rstb.2014.0182
Ma WJ, Hashii M, Munesue T et al (2013) Non-synonymous single-nucleotide variations of the human oxytocin receptor gene and autism spectrum disorders: a case-control study in a Japanese population and functional analysis. Mol Autism 4(1):22. doi:10.1186/2040-2392-4-22
Mak P, Broussard C, Vacy K et al (2012) Modulation of anxiety behavior in the elevated plus maze using peptidic oxytocin and vasopressin receptor ligands in the rat. J Psychopharmacol 26(4):532–542. doi:10.1177/0269881111416687
Malik RU, Ritt M, DeVree BT et al (2013) Detection of G protein-selective G protein-coupled receptor (GPCR) conformations in live cells. J Biol Chem 288(24):17167–17178. doi:10.1074/jbc.M113.464065
Manning M, Misicka A, Olma A et al (2012) Oxytocin and vasopressin agonists and antagonists as research tools and potential therapeutics. J Neuroendocrinol 24(4):609–628. doi:10.1111/j.1365-2826.2012.02303.x
Marchese A, Paing MM, Temple BR et al (2008) G protein-coupled receptor sorting to endosomes and lysosomes. Annu Rev Pharmacol Toxicol 48:601–629. doi:10.1146/annurev.pharmtox.48.113006.094646
Melis MR, Succu S, Iannucci U et al (1997) Oxytocin increases nitric oxide production in the paraventricular nucleus of the hypothalamus of male rats: correlation with penile erection and yawning. Regul Pept 69(2):105–111
Mens WB, Witter A, van Wimersma Greidanus TB (1983) Penetration of neurohypophyseal hormones from plasma into cerebrospinal fluid (CSF): half-times of disappearance of these neuropeptides from CSF. Brain Res 262(1):143–149
Milligan G (1993) Regional distribution and quantitative measurement of the phosphoinositidase C-linked guanine nucleotide binding proteins G11 alpha and Gq alpha in rat brain. J Neurochem 61(3):845–851
Moncada S, Higgs A (1993) The L-arginine-nitric oxide pathway. N Engl J Med 329(27):2002–2012. doi:10.1056/NEJM199312303292706
Muhlethaler M, Sawyer WH, Manning MM et al (1983) Characterization of a uterine-type oxytocin receptor in the rat hippocampus. Proc Natl Acad Sci U S A 80(21):6713–6717
Muth S, Fries A, Gimpl G (2011) Cholesterol-induced conformational changes in the oxytocin receptor. Biochem J 437(3):541–553. doi:10.1042/BJ20101795
Neumann ID, Slattery DA (2016) Oxytocin in general anxiety and social fear: a translational approach. Biol Psychiatry 79(3):213–221. doi:10.1016/j.biopsych.2015.06.004
Neumann I, Russell JA, Wolff B et al (1991) Naloxone increases the release of oxytocin, but not vasopressin, within limbic brain areas of conscious parturient rats: a push-pull perfusion study. Neuroendocrinology 54(6):545–551
Oakley RH, Laporte SA, Holt JA et al (2001) Molecular determinants underlying the formation of stable intracellular G protein-coupled receptor-beta-arrestin complexes after receptor endocytosis*. J Biol Chem 276(22):19452–19460. doi:10.1074/jbc.M101450200
Oates J, Watts A (2011) Uncovering the intimate relationship between lipids, cholesterol and GPCR activation. Curr Opin Struct Biol 21(6):802–807. doi:10.1016/j.sbi.2011.09.007
Okude J, Ueda T, Kofuku Y et al (2015) Identification of a conformational equilibrium that determines the efficacy and functional selectivity of the mu-opioid receptor. Angew Chem Int Ed Engl 54(52):15771–15776. doi:10.1002/anie.201508794
Palczewski K, Kumasaka T, Hori T et al (2000) Crystal structure of rhodopsin: a G protein-coupled receptor. Science 289(5480):739–745
Passoni I, Leonzino M, Gigliucci V et al (2016) Carbetocin is a functional selective Gq agonist that does not promote oxytocin receptor recycling after inducing beta-arrestin-independent internalisation. J Neuroendocrinol 28(4). doi:10.1111/jne.12363
Pearlmutter AF, Soloff MS (1979) Characterization of the met al ion requirement for oxytocin-receptor interaction in rat mammary gland membranes. J Biol Chem 254(10):3899–3906
Qian A, Wang W, Sanborn BM (1998) Evidence for the involvement of several intracellular domains in the coupling of oxytocin receptor to G alpha(q/11). Cell Signal 10(2):101–105
Reversi A, Rimoldi V, Marrocco T et al (2005) The oxytocin receptor antagonist atosiban inhibits cell growth via a “biased agonist” mechanism. J Biol Chem 280(16):16311–16318. doi:10.1074/jbc.M409945200
Reversi A, Rimoldi V, Brambillasca S et al (2006) Effects of cholesterol manipulation on the signaling of the human oxytocin receptor. Am J Physiol Regul Integr Comp Physiol 291(4):R861–R869. doi:10.1152/ajpregu.00333.2006
Rilling JK, Young LJ (2014) The biology of mammalian parenting and its effect on offspring social development. Science 345(6198):771–776. doi:10.1126/science.1252723
Rimoldi V, Reversi A, Taverna E et al (2003) Oxytocin receptor elicits different EGFR/MAPK activation patterns depending on its localization in caveolin-1 enriched domains. Oncogene 22(38):6054–6060. doi:10.1038/sj.onc.1206612
Rivera C, Voipio J, Payne JA et al (1999) The K+/Cl− co-transporter KCC2 renders GABA hyperpolarizing during neuronal maturation. Nature 397(6716):251–255. doi:10.1038/16697
Romero-Fernandez W, Borroto-Escuela DO, Agnati LF et al (2013) Evidence for the existence of dopamine D2-oxytocin receptor heteromers in the ventral and dorsal striatum with facilitatory receptor-receptor interactions. Mol Psychiatry 18(8):849–850. doi:10.1038/mp.2012.103
Ross HE, Cole CD, Smith Y et al (2009) Characterization of the oxytocin system regulating affiliative behavior in female prairie voles. Neuroscience 162(4):892–903. doi:10.1016/j.neuroscience.2009.05.055
Russell JA, Neumann I, Landgraf R (1992) Oxytocin and vasopressin release in discrete brain areas after naloxone in morphine-tolerant and -dependent anesthetized rats: push-pull perfusion study. J Neurosci 12(3):1024–1032
Sala M, Braida D, Lentini D et al (2011) Pharmacologic rescue of impaired cognitive flexibility, social deficits, increased aggression, and seizure susceptibility in oxytocin receptor null mice: a neurobehavioral model of autism. Biol Psychiatry 69(9):875–882. doi:10.1016/j.biopsych.2010.12.022
Sanborn BM (2001) Hormones and calcium: mechanisms controlling uterine smooth muscle contractile activity. The Litchfield lecture. Exp Physiol 86(2):223–237
Sanborn BM, Dodge K, Monga M et al (1998) Molecular mechanisms regulating the effects of oxytocin on myometrial intracellular calcium. Adv Exp Med Biol 449:277–286
Satoh Y, Endo S, Nakata T et al (2011) ERK2 contributes to the control of social behaviors in mice. J Neurosci 31(33):11953–11967. doi:10.1523/JNEUROSCI.2349-11.2011
Shenoy SK, Lefkowitz RJ (2005) Seven-transmembrane receptor signaling through beta-arrestin. Sci STKE 2005(308):cm10. doi:10.1126/stke.2005/308/cm10
Shiina T, Arai K, Tanabe S et al (2001) Clathrin box in G protein-coupled receptor kinase 2. J Biol Chem 276(35):33019–33026. doi:10.1074/jbc.M100140200
Skuse DH, Lori A, Cubells JF et al (2014) Common polymorphism in the oxytocin receptor gene (OXTR) is associated with human social recognition skills. Proc Natl Acad Sci U S A 111(5):1987–1992. doi:10.1073/pnas.1302985111
Smith MP, Ayad VJ, Mundell SJ et al (2006) Internalization and desensitization of the oxytocin receptor is inhibited by Dynamin and clathrin mutants in human embryonic kidney 293 cells. Mol Endocrinol 20(2):379–388. doi:10.1210/me.2005-0031
Smith TH, Coronel LJ, Li JG et al (2016) Protease-activated receptor-4 signaling and trafficking is regulated by the Clathrin adaptor protein complex-2 independent of beta-Arrestins. J Biol Chem 291(35):18453–18464. doi:10.1074/jbc.M116.729285
Sofroniew MV (1983) Morphology of vasopressin and oxytocin neurones and their central and vascular projections. Prog Brain Res 60:101–114. doi:10.1016/S0079-6123(08)64378-2
Srivastava A, Gupta B, Gupta C et al (2015) Emerging functional divergence of beta-arrestin isoforms in GPCR function. Trends Endocrinol Metab 26(11):628–642. doi:10.1016/j.tem.2015.09.001
Strakova Z, Soloff MS (1997) Coupling of oxytocin receptor to G proteins in rat myometrium during labor: Gi receptor interaction. Am J Physiol 272(5 Pt 1):E870–E876
Sun J, Nan G (2016) The mitogen-activated protein kinase (MAPK) signaling pathway as a discovery target in stroke. J Mol Neurosci 59(1):90–98. doi:10.1007/s12031-016-0717-8
Swanson LW, Sawchenko PE (1983) Hypothalamic integration: organization of the paraventricular and supraoptic nuclei. Annu Rev Neurosci 6:269–324. doi:10.1146/annurev.ne.06.030183.001413
Takayanagi Y, Yoshida M, Bielsky IF et al (2005) Pervasive social deficits, but normal parturition, in oxytocin receptor-deficient mice. Proc Natl Acad Sci U S A 102(44):16096–16101. doi:10.1073/pnas.0505312102
Terenzi MG, Ingram CD (2005) Oxytocin-induced excitation of neurones in the rat central and medial amygdaloid nuclei. Neuroscience 134(1):345–354. doi:10.1016/j.neuroscience.2005.04.004
Terrillon S, Durroux T, Mouillac B et al (2003) Oxytocin and vasopressin V1a and V2 receptors form constitutive homo- and heterodimers during biosynthesis. Mol Endocrinol 17(4):677–691. doi:10.1210/me.2002-0222
Thibonnier M, Conarty DM, Preston JA et al (1999) Human vascular endothelial cells express oxytocin receptors. Endocrinology 140(3):1301–1309. doi:10.1210/endo.140.3.6546
Thurm A, Tierney E, Farmer C et al (2016) Development, behavior, and biomarker characterization of Smith-Lemli-Opitz syndrome: an update. J Neurodev Disord 8:12. doi:10.1186/s11689-016-9145-x
Tierney E, Bukelis I, Thompson RE et al (2006) Abnormalities of cholesterol metabolism in autism spectrum disorders. Am J Med Genet B Neuropsychiatr Genet 141B(6):666–668. doi:10.1002/ajmg.b.30368
Tobin VA, Arechaga G, Brunton PJ et al (2014) Oxytocinase in the female rat hypothalamus: a novel mechanism controlling oxytocin neurones during lactation. J Neuroendocrinol 26(4):205–216. doi:10.1111/jne.12141
Tolchard S, Ingram CD (1993) Electrophysiological actions of oxytocin in the dorsal vagal complex of the female rat in vitro: changing responsiveness during the oestrous cycle and after steroid treatment. Brain Res 609(1–2):21–28
Tomizawa K, Iga N, Lu YF et al (2003) Oxytocin improves long-lasting spatial memory during motherhood through MAP kinase cascade. Nat Neurosci 6(4):384–390. doi:10.1038/nn1023
Tyzio R, Nardou R, Ferrari DC et al (2014) Oxytocin-mediated GABA inhibition during delivery attenuates autism pathogenesis in rodent offspring. Science 343(6171):675–679. doi:10.1126/science.1247190
Valeeva G, Valiullina F, Khazipov R (2013) Excitatory actions of GABA in the intact neonatal rodent hippocampus in vitro. Front Cell Neurosci 7:20. doi:10.3389/fncel.2013.00020
Van den Burg EH, Stindl J, Grund T et al (2015) Oxytocin stimulates extracellular Ca2+ influx through TRPV2 channels in hypothalamic neurons to exert its anxiolytic effects. Neuropsychopharmacology 40(13):2938–2947. doi:10.1038/npp.2015.147
Veenema AH, Neumann ID (2008) Central vasopressin and oxytocin release: regulation of complex social behaviours. Prog Brain Res 170:261–276. doi:10.1016/S0079-6123(08)00422-6
Villar VA, Cuevas S, Zheng X et al (2016) Localization and signaling of GPCRs in lipid rafts. Methods Cell Biol 132:3–23. doi:10.1016/bs.mcb.2015.11.008
Wang YF, Hatton GI (2007) Dominant role of betagamma subunits of G-proteins in oxytocin-evoked burst firing. J Neurosci 27(8):1902–1912. doi:10.1523/JNEUROSCI.5346-06.2007
Watari K, Nakaya M, Nishida M et al (2013) Beta-arrestin2 in infiltrated macrophages inhibits excessive inflammation after myocardial infarction. PLoS One 8(7):e68351. doi:10.1371/journal.pone.0068351
Wettschureck N, Moers A, Hamalainen T et al (2004) Heterotrimeric G proteins of the Gq/11 family are crucial for the induction of maternal behavior in mice. Mol Cell Biol 24(18):8048–8054. doi:10.1128/MCB.24.18.8048-8054.2004
Wigger A, Sanchez MM, Mathys KC et al (2004) Alterations in central neuropeptide expression, release, and receptor binding in rats bred for high anxiety: critical role of vasopressin. Neuropsychopharmacology 29(1):1–14. doi:10.1038/sj.npp.1300290
Wilkie TM, Scherle PA, Strathmann MP et al (1991) Characterization of G-protein alpha subunits in the Gq class: expression in murine tissues and in stromal and hematopoietic cell lines. Proc Natl Acad Sci U S A 88(22):10049–10053
Wilson BC, Terenzi MG, Ingram CD (2005) Differential excitatory responses to oxytocin in sub-divisions of the bed nuclei of the stria terminalis. Neuropeptides 39(4):403–407. doi:10.1016/j.npep.2005.04.001
Wolfe BL, Trejo J (2007) Clathrin-dependent mechanisms of G protein-coupled receptor endocytosis. Traffic 8(5):462–470. doi:10.1111/j.1600-0854.2007.00551.x
Wrzal PK, Devost D, Petrin D et al (2012a) Allosteric interactions between the oxytocin receptor and the beta2-adrenergic receptor in the modulation of ERK1/2 activation are mediated by heterodimerization. Cell Signal 24(1):342–350. doi:10.1016/j.cellsig.2011.09.020
Wrzal PK, Goupil E, Laporte SA et al (2012b) Functional interactions between the oxytocin receptor and the beta2-adrenergic receptor: implications for ERK1/2 activation in human myometrial cells. Cell Signal 24(1):333–341. doi:10.1016/j.cellsig.2011.09.019
Yoshida M, Takayanagi Y, Inoue K et al (2009) Evidence that oxytocin exerts anxiolytic effects via oxytocin receptor expressed in serotonergic neurons in mice. J Neurosci 29(7):2259–2271. doi:10.1523/JNEUROSCI.5593-08.2009
Young LJ, Wang Z (2004) The neurobiology of pair bonding. Nat Neurosci 7(10):1048–1054. doi:10.1038/nn1327
Zhong M, Navratil AM, Clay C et al (2004) Residues in the hydrophilic face of putative helix 8 of oxytocin receptor are important for receptor function. Biochemistry 43(12):3490–3498. doi:10.1021/bi035899m
Zhou XB, Lutz S, Steffens F et al (2007) Oxytocin receptors differentially signal via Gq and Gi proteins in pregnant and nonpregnant rat uterine myocytes: implications for myometrial contractility. Mol Endocrinol 21(3):740–752. doi:10.1210/me.2006-0220
Zocher M, Fung JJ, Kobilka BK et al (2012) Ligand-specific interactions modulate kinetic, energetic, and mechanical properties of the human beta2 adrenergic receptor. Structure 20(8):1391–1402. doi:10.1016/j.str.2012.05.010
Zoicas I, Slattery DA, Neumann ID (2014) Brain oxytocin in social fear conditioning and its extinction: involvement of the lateral septum. Neuropsychopharmacology 39(13):3027–3035. doi:10.1038/npp.2014.156
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Busnelli, M., Chini, B. (2017). Molecular Basis of Oxytocin Receptor Signalling in the Brain: What We Know and What We Need to Know. In: Hurlemann, R., Grinevich, V. (eds) Behavioral Pharmacology of Neuropeptides: Oxytocin. Current Topics in Behavioral Neurosciences, vol 35. Springer, Cham. https://doi.org/10.1007/7854_2017_6
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