**Neuregulin-1 (Nrg1): An Emerging Regulator of Prolactin (PRL) Secretion**

Weijiang Zhao

82 Prolactin

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Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/54716

### **1. Introduction**

#### **1.1. Definition and structure of Neuregulin-1 (Nrg1)**

Hypothalamus-derived dopamine and thyrotrophin-releasing hormone (TRH) have long been considered the main sources of prolactin (PRL) regulators in the anterior pituitary, whereas other substances also modulate PRL expression and secretion (Borrelli et al., 1992; Cai et al., 1999; Spuch et al., 2006). Recently, Vlotides for the first time observed that recombinant Nrg1 can control PRL secretion from rat RPL and growth hormone (GH) secreting lactosomatotroph GH3 cells, suggesting the emerging role of Nrg1 as a PRL regulator (Vlotides et al., 2009).

Neuregulins are homologous to epidermal growth factor (EGF) and are mainly encoded by four alternatively spliced genes: NRG-1 to -4 (Orr-Urtreger et al., 1993). Diverse splicing of the NRG-1 gene gives rise to at least six main types of Nrg1 (types I–VI) with ectodomain variation, whereas type I to III Nrg1. are the most intensively investigated. All types of Nrg1 contain an EGF-like domain, which can be classified as either α or β (Jacobsen et al., 1996; Rosnack et al., 1994). Distinct from soluble Nrg1, a membrane-tethered Nrg1 precursor has been identified that contains a transmembrane (TM) domain and an intracellular domain (ICD). The ICD can be further characterized as ICD a, b and c. The structure that links the ectodomain and the transmembrane (TM) domain is called a stalk (S), which can be further classified as S1, S2 and S4. Proteolysis of the Nrg1 precursor, a tightly regulated process, releases the soluble domains and leads to formation of autocrineparacrine loops. However, recruitment of S3, which contains the stop codon, terminates the extension of the ectodomain into the cytoplasm and thus leads to the formation of non-membrane anchored Nrg1α/β **(See Fig 1)**.

© 2013 Zhao, licensee InTech. This is an open access chapter distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Neuregulin-1 (Nrg1): An Emerging Regulator of Prolactin (PRL) Secretion 85

**Figure 2. Schematic of type I- III Nrg1 interaction with their receptors.** The initial proteolysis site was

**2.1. Expression and localization of Nrg1 and its receptor in the anterior pituitary** 

The Nrg1-ErbB signaling pathway has a critical role in organ development, cell differentiation and tumorigenesis. Neuregulins have previously been described in the nervous system, especially in the cortex, spinal cord and hypothalamus. In the hypothalamus, ARIA (or Nrg1α and β) was expressed in neurons with processes projecting to the posterior pituitary gland but not in those without these projections, suggesting that hypothalamus-derived Neuregulin regulates certain functions of the pituitary (Bernstein et al., 2006; Corfas et al., 1995). Furthermore, Nrg1 receptors were reported to be expressed in hypothalamic astrocytes, where their activation as a result of paracrine Nrg1 stimulation is essential for stimulating secretion of luteinising hormone-releasing hormone (LHRH), intrapituitary gonadotrophin secretion and normal sexual puberty (Bernstein et al., 2006;

indicated by the arrow, and the site for second proteolysis was indicated by the arrow head.

**2. Endogenous expression of Nrg1 in the anterior pituitary and rat** 

**lactosomatotroph GH3 cells** 

**of rat and non-human primates** 

Prevot et al., 2003).

**Figure 1. Schematic of type I- III Nrg1** Diverse splicing of NRG-1 gene gives rise to Type I-III Nrg1s, whose structures were schematically diagrammed. α, EGF-like domain α; β, EGF-like domain β; Ig, Iglike domain; s, stalk domain; sp, spacer domain.

### **1.2. Interaction of Nrg1 with its cognate receptors and related biological functions**

The bioactivity of Nrg1 is mainly mediated by homodimers comprised of their cognate receptors ErbB4 (Hahn et al., 2006) or ErbB3/ErbB2 and ErbB4/ErbB2 heterodimeric complexes (Liu et al., 2002) (See Fig 2). Nrg1 was found to specifically activate the tyrosine kinase receptor ErbB2 as a growth factor extracted from the conditioned medium of a human breast tumor cell line (Holmes et al., 1992). It exerts mitogenic activity on cultured Schwann cells as type II Nrg1 (Glial growth factor, GGF) purified from the brain and bovine pituitary anterior lobe (Lemake et al., 1984). The acetylcholine receptor-inducing activity protein (ARIA), another Nrg1 type, was shown to promote acetylcholine receptor synthesis in cultured skeletal muscle and myotubes (Jessell et al., 1979; Usdin et al., 1986). The ligandreceptor interaction initiates a complex intracellular signaling cascade in which extracellular signal-regulated kinase (ERK), serine/threonine protein kinase (AKT), mitogen-activated protein kinase (MAPK), phosphatidyl-inositol 3-kinase γ (PIK3γ), protein kinase C (PKC), and Janus kinase-signal transducers and activators of transcription (Jak-STAT) are activated. Activation of this signaling pathway leads to, among other events, tumorigenic development, cell cycle arrest, cell proliferation, differentiation, and anti-apoptotic processes (Peles et al., 1993; Liu and Kern et al., 2002; Puricelli et al., 2002). Recently, Nrg*β*1 has been reported to signal mitogenesis of cortical astrocytes through ErbB1ErbB3 heterodimeric complex (Sharif et al., 2009).

**Figure 1. Schematic of type I- III Nrg1** Diverse splicing of NRG-1 gene gives rise to Type I-III Nrg1s, whose structures were schematically diagrammed. α, EGF-like domain α; β, EGF-like domain β; Ig, Ig-

The bioactivity of Nrg1 is mainly mediated by homodimers comprised of their cognate receptors ErbB4 (Hahn et al., 2006) or ErbB3/ErbB2 and ErbB4/ErbB2 heterodimeric complexes (Liu et al., 2002) (See Fig 2). Nrg1 was found to specifically activate the tyrosine kinase receptor ErbB2 as a growth factor extracted from the conditioned medium of a human breast tumor cell line (Holmes et al., 1992). It exerts mitogenic activity on cultured Schwann cells as type II Nrg1 (Glial growth factor, GGF) purified from the brain and bovine pituitary anterior lobe (Lemake et al., 1984). The acetylcholine receptor-inducing activity protein (ARIA), another Nrg1 type, was shown to promote acetylcholine receptor synthesis in cultured skeletal muscle and myotubes (Jessell et al., 1979; Usdin et al., 1986). The ligandreceptor interaction initiates a complex intracellular signaling cascade in which extracellular signal-regulated kinase (ERK), serine/threonine protein kinase (AKT), mitogen-activated protein kinase (MAPK), phosphatidyl-inositol 3-kinase γ (PIK3γ), protein kinase C (PKC), and Janus kinase-signal transducers and activators of transcription (Jak-STAT) are activated. Activation of this signaling pathway leads to, among other events, tumorigenic development, cell cycle arrest, cell proliferation, differentiation, and anti-apoptotic processes (Peles et al., 1993; Liu and Kern et al., 2002; Puricelli et al., 2002). Recently, Nrg*β*1 has been reported to signal mitogenesis of cortical astrocytes through ErbB1ErbB3 heterodimeric

**1.2. Interaction of Nrg1 with its cognate receptors and related biological** 

like domain; s, stalk domain; sp, spacer domain.

**functions** 

complex (Sharif et al., 2009).

**Figure 2. Schematic of type I- III Nrg1 interaction with their receptors.** The initial proteolysis site was indicated by the arrow, and the site for second proteolysis was indicated by the arrow head.
