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  • In addition to gonadotropes GnRHRs have also been detected

    2021-09-17

    In addition to gonadotropes, GnRHRs have also been detected on somatotropes, lactotropes, thyrotropes, melanotropes, somatolactin (SL) cells, and/or corticotropes using immunohistochemical, radioligand-binding, or mRNA expression approaches across species; including fishes, rats, and humans (La Rosa et al., 2000, Parhar et al., 2002, Parhar, 2005, Stefano et al., 1999, Cook et al., 1991, Childs and Unabia, 1997). In tilapia, from which three GnRHRs have been cloned, expression of more than one endogenous isoform of GnRHRs have also been reported in all pituitary cell-types using laser-capture single cell PCR and with SL-, thyrotropin (TSH)-, and corticotropin (ACTH)-cells expressing all three GnRHR forms (Parhar et al., 2005). Furthermore, GnRH-immunoreactive fibres have been mapped to the vicinity of all adenohypophyseal cell-types in the pituitary of the Nile perch (Mousa and Mousa, 2003). Although GnRHRs may not be found in all other pituitary cell-types in species where extra-gonadotropic GnRHRs are present, these observations indicate that GnRH actions are not restricted to gonadotropes in some species. Understanding how multiple GnRHs signal through shared GnRHRs to regulate pituitary cell functions not only contributes to the knowledge of GnRH actions on the pituitary, such information is also potentially relevant to our understanding of extrapituitary GnRH influences in physiological, as well as clinical, conditions. For example, two GnHRs (mGnRH and cGnRH-II) are expressed in the human ovary where they regulate ovarian steroidogenesis and cell proliferation (Metallinou et al., 2007) and cGnRH-II has been shown to be important in the regulation of ovarian cancers (So et al., 2008, Poon et al., 2011).
    GnRH-stimulated signalling in gonadotropes GPCRs, including GnRHRs, operate as a transduction unit containing the transmembrane-spanning receptor, a heterotrimeric G protein (Gαβγ), and effectors that promote intracellular changes leading to a cellular response (Audet and Bouvier, 2012). Following agonist-receptor binding and the subsequent nucleotide exchange that converts Gα from an inactive GDP-bound conformation to an active GTP-bound conformation that can modulate the activity of effector proteins, the heterotrimeric Gαβγ complex dissociates into free Gα and Gβγ subunits (Oldham and Hamm, 2008). Distinct CFTRinh-172 of Gα subunits have also been shown to couple to conserved intracellular signalling effectors, including: adenylyl cyclases (ACs; Gαs and Gαi/o); phosphodiesterases (PDEs; Gαi/o); phospholipase Cβ (PLC; Gαq/11) as well as its downstream effector systems protein kinase Cs (PKCs; Gαq/11) and calcium (Ca2+; Gαq/11); and members of the Rho-family of small GTPases (Gα12/13; Marinissen and Gutkind, 2001). Independent of signalling downstream of the Gα subunits, Gβγ heterodimers also directly associate with downstream effectors to regulate distinct aspects of cellular physiology (Khan et al., 2013). Thus, a diverse array of signal transduction cascades can be activated unpon GPCR activation. These fundamentals of GPCR activation are important for understanding how the diversity of GnRH-stimulated signalling is manifested.
    GnRH-stimulated signalling in somatotropes
    GnRH-stimulated signalling in lactotropes
    Possible actions of GnRH on thyrotropes, corticotropes, melanotropes, and somatolactin cells Although not thoroughly examined, there are indications that GnRHs can affect thyrotrope, corticotrope, and somatolactin cell functions in vertebrates. Ultrastructural evidence suggests that GnRH increases the activities of thyrotropes in hemipituitary of eel in vitro (Olivereau et al., 1986). GnRH also enhanced TSH release from adult bullfrog pituitary cells but not from larval pituitary cells (Okada et al., 2009). Treatment with desensitizing doses of mGnRH agonists significantly reduced free T3 levels as well as free T3 to free T4 ratios in children with idiopathic precocious puberty although changes in TSH levels were not significant (Massart et al., 2007). On the other hand, mGnRH stimulated ACTH secretion in some patients with hypothyroidism (Ban et al., 2000) and from perifused pituitary tumor cells obtained from patients with Cushing's disease (Oki et al., 1981). GnRH immunoreactive fibers innervate the pars intermedia of cichlids and the Nile perch, and GnRH also stimulates SL release, as well as increases SL mRNA expression, in some fish species in a sexual stage-dependent manner (Taniyama et al., 2000, Mousa and Mousa, 2003, Bhandari et al., 2003, Onuma et al., 2005, Kitahashi et al., 2007, Cánepa et al., 2008). Likewise, GnRH stimulates SL release from rainbow trout pituitary organ cultures when the SL secretion rate has been suppressed by dopamine (Kakizawa et al., 1997). The cellular and intracellular mechanisms mediating these effects of GnRH on TSH, ACTH, and SL release and/or synthesis have not been evaluated. In addition, nothing is known at present regarding whether and how GnRH may regulate MSH release or synthesis despite the reported presence of GnRHRs on MSH cells in fish (see Section 2 above).