REVIEW: Oxytocin: Crossing the bridge between basic science and pharmacotherapy

Abstract

Is oxytocin the hormone of happiness? Probably not. However, this small nine amino acid peptide is involved in a wide variety of physiological and pathological functions such as sexual activity, penile erection, ejaculation, pregnancy, uterus contraction, milk ejection, maternal behavior, osteoporosis, diabetes, cancer, social bonding, and stress, which makes oxytocin and its receptor potential candidates as targets for drug therapy. In this review, we address the issues of drug design and specificity and focus our discussion on recent findings on oxytocin and its heterotrimeric G protein-coupled receptor OTR. In this regard, we will highlight the following topics: (i) the role of oxytocin in behavior and affectivity, (ii) the relationship between oxytocin and stress with emphasis on the hypothalamo-pituitary-adrenal axis, (iii) the involvement of oxytocin in pain regulation and nociception, (iv) the specific action mechanisms of oxytocin on intracellular Ca²(+) in the hypothalamo neurohypophysial system (HNS) cell bodies, (v) newly generated transgenic rats tagged by a visible fluorescent protein to study the physiology of vasopressin and oxytocin, and (vi) the action of the neurohypophysial hormone outside the central nervous system, including the myometrium, heart and peripheral nervous system. As a short nine amino acid peptide, closely related to its partner peptide vasopressin, oxytocin appears to be ideal for the design of agonists and antagonists of its receptor. In addition, not only the hormone itself and its binding to OTR, but also its synthesis, storage and release can be endogenously and exogenously regulated to counteract pathophysiological states. Understanding the fundamental physiopharmacology of the effects of oxytocin is an important and necessary approach for developing a potential pharmacotherapy.

Figure 1

Constructs of the fluorescent protein fusion genes used for transgenic animal models. (A) Structure of the arginine vasopressin (AVP)‐enhanced green fluorescent protein (eGFP) transgene. In the AVP‐eGFP transgene, the eGFP coding region is inserted at the frame in the middle of exon III. “Copyright 2005, The Endocrine Society” modified and reproduced with permission from Ref. [94]. (B) Structure of the c‐fos‐monomeric red fluorescent protein 1 (mRFP1) transgene. In the c‐fos‐mRFP1 transgene, the mRFP1 coding region is inserted at the frame at the end of exon IV followed by the stop codon. “Copyright 2009, The Endocrine Society” reproduced with permission from Ref. [98]. (C) Structure of the oxytocin‐enhanced cyan fluorescent protein (eCFP) transgene. In the oxytocin‐eCFP transgene, the eCFP coding region is inserted at the frame in the middle of exon III, after the oxytocin and the bulk of the neurophysin coding regions. “Copyright 2010, Society for Endocrinology” modified and reproduced with permission from Ref. [97].

Figure 2

Schematic diagram of OTR‐linked signaling pathways. Oxytocin receptor (OTR) activation leads to three different GTP‐binding protein mechanisms. The major mechanism is mediated by the G_q/PLC/InsP₃ pathway. When oxytocin binds to OTR, it activates G_αq/11 and then phospholipase C (PLC), which induces the cleavage of PIP2 to inositoltrisphosphate (InsP₃) and diacylglycerol (DAG). InsP₃ induces Ca²⁺ release from Ca²⁺ stores via InsP₃R and, in some cells, causes Ca²⁺‐induced Ca²⁺ release (CICR) via the ryanodine receptor (RyR). The activation of G_q also causes membrane depolarization*, which, in turn, activates VGCCs and then facilitates Ca²⁺ entry through VGCCs. Thus, increased cytosolic Ca²⁺ ([Ca²⁺]_i) stimulates CaMK after binding to the Ca²⁺ binding protein Calmodulin. The Ca²⁺/CaM complex then activates CaMK and causes various cellular responses, such as smooth muscle contractions, or induces the activation of several different types of enzymes, such as NOS or PI3K. DAG causes protein kinase C (PKC) activation and also various cellular responses. Additional pathways activated through the OTR include the MAP‐kinase (MAPK) and the Rho kinase pathways. The increased transcription of COX2 mediates the increased production and secretion of prostaglandins. The OTR‐mediated opening of Ca²⁺ channels is likely mediated through free G_βγ subunits. The OT receptor is known to be coupled with the other G proteins, G_s and G_i, both of which are linked with the AC pathway. The proliferative effects involve MAPK‐mediated activation of specific gene transcription. The trophic effects are mediated via a PKC‐mediated activation of eEF2. Activation of the Rho and MAP kinase pathways, the increase in intracellular Ca²⁺ and the increased prostaglandin secretion all contribute to the contractile effects. The antiproliferative effects observed in certain cells types appear to be mediated via αi G protein subunits. For further details, see the text and the references therein. The solid red lines and broken blue lines indicate activation and inhibition, respectively. Abbreviations: VGCC = Voltage‐gated Ca²⁺ channel; InsP₃R = InsP₃ receptor; RyR = Ryanodine receptor; PLC = Phospholipase C; DAG = Diacyl glycerol; Ca²⁺/CaM = Ca²⁺‐calmodulin complex; CaMK = Ca²⁺/Calmodulin‐dependent protein kinase; NOS = NO synthase; PLA₂= Phospholipase A₂; COX2 = Cyclooxygenase 2; AC = Adenylate cyclase; PI3K = Phosphoinositide 3‐kinase; ROK = Rho kinase. ^#The G_i mediated anti‐proliferative effect has been described as dependent on epidermal growth factor receptor (EGFR) transactivation and mitogen‐activated protein kinase (MAPK) activation via a PLC/PI3K/cellular sarcoma tyrosine kinase (c‐Src)‐dependent pathway that ultimately leads to a sustained activation of the cell cycle inhibitor [158].* The mechanisms of the oxytocin‐induced membrane depolarization have been explored in various types of neuronal cells, and they are classified as follows:
1. Suppression of voltage‐gated K⁺ currents
2. Activation of non‐selective cationic currents
3. Activation of sustained Na⁺‐dependent currents (could be the same as 2)
Inhibition of GABA_A receptors (this would depolarize if GABA acts as a tonic inhibitory modulator).