Invited reviewCrosstalk between receptor tyrosine kinases (RTKs) and G protein-coupled receptors (GPCR) in the brain: Focus on heteroreceptor complexes and related functional neurotrophic effects
Introduction
Cells utilize a plethora of biochemical mechanisms to transduce and integrate extracellular and intracellular signals into their phenotypic response patterns under several physiological or pathological conditions. In addition to ionotropic receptors, which allows ions to flow selectively through the cell membrane, the extracellular signals are transduced by two major classes of cell surface transmembrane proteins: G protein-coupled receptors (GPCRs) and receptor tyrosine kinases (RTKs) (Uings and Farrow, 2000). It is now widely recognized that the two classes of receptors are forming heteroreceptor complexes producing an intense bidirectional cross-communication in the cell, which generates signaling mechanisms that connect and diversify the canonical signal transduction pathways activated by the single receptor (Borroto-Escuela et al., 2017a, Pyne and Pyne, 2011). On the basis of this bidirectional inter-receptor crosstalk, GPCR can transactivate RTKs and stimulate their signaling activity, such as the extracellular signal-regulated kinase (ERK) cascade, while RTKs can signal through the involvement of GPCR signaling molecules, such as heterotrimeric G proteins and arrestins (Borroto-Escuela et al., 2012b, Tilley et al., 2009). Nowadays, numerous reports have described several heteroreceptor complexes leading to transactivation mechanisms taking place in different cell types and playing important roles in both cell physiology and pathology (Borroto-Escuela et al., 2017a, Borroto-Escuela et al., 2011, Cattaneo et al., 2014, Delcourt et al., 2007a, Fuxe et al., 2014a, Fuxe and Borroto-Escuela, 2016a, Fuxe and Borroto-Escuela, 2016b, Fuxe et al., 2014c, Pyne and Pyne, 2011, Shah and Catt, 2004). Here, we will focus on GPCR and RTKs forming heteroreceptor complexes producing GPCR-mediated transactivation of RTKs in the central nervous system (CNS) and on its functional effects in controlling a variety of cellular effects during development, proliferation, differentiation, migration, survival, repair, synaptic transmission and plasticity.
Section snippets
GPCR activation and signal transduction
GPCRs, the largest family of membrane proteins, regulate a wide range of intracellular signaling pathways in response to diverse ligands, ranging from small molecules and photons to peptides and proteins, thus playing an essential role in cell pathophysiology and in the therapy of several diseases (Hilger et al., 2018, Pierce et al., 2002). All GPCRs comprise seven-transmembrane α-helical domains (7TM), an amino-terminal extracellular domain and an intra-cellular carboxyl terminus domain (
RTKs activation and signal transduction
All RTKs share a similar structure, with ligand-binding domains in the extracellular region, a single transmembrane helix, and a cytoplasmic region that includes the protein tyrosine kinase (TK) domain and additional regulatory regions. In general, ligand binding activates RTKs by inducing receptor dimerization (Ullrich and Schlessinger, 1990), leading to the activation of the intracellular TK domain and the subsequent phosphorylation of specific sites which produce the recruitment of
Heteroreceptor complexes: overview
The existence of direct interactions between different receptors potentially forming heteroreceptor complexes with allosteric receptor–receptor interactions was hypothesized by Agnati and Fuxe in the 1980s, based on the ability of neuropeptides to modulate the binding characteristics of subtypes of monoamine receptors in membrane preparations (Agnati et al., 1980, Fuxe and Agnati, 1985, Fuxe et al., 1983). The term allostery (Kenakin, 2010, Tsai et al., 2009) indicates a long-distance
Transactivation machanisms: overview
A wide range of data has demonstrated that GPCRs and RTKs, which activate similar signaling molecules and regulate the same cell functions, do not operate isolated but they may interact each other, generating a cross-communication that integrates and coordinates informations from diverse sources, under both physiological or pathological conditions, thus providing a complex control over several regulatory cellular mechanisms (Lowes et al., 2002, Shah and Catt, 2004). In fact, it is now well
GPCR-Trk receptors complexes and functional transactivation
The neurotrophins nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin 3 (NT3) and neurotrophin 4 (NT4) are a family of proteins essential for the development of the CNS. Indeed, neurotrophins signaling is a key factor in regulating neuronal survival, proliferation, differentiation, neuritis growth, synaptic function and synaptic plasticity (Huang and Reichardt, 2001, Lewin and Barde, 1996, Skaper, 2008, Thoenen, 1995). Each neurotrophin can signal through two
GPCR-EGF receptors complexes and functional transactivation
EGFR/erbB1 is one of four members of the ErbB family of TKRs and is activated by ligand-dependent homo- and heterodimerization (Olayioye et al., 2000, Schlessinger, 2002, Yarden and Sliwkowski, 2001). ErbB proteins are transmembrane receptors with an extracellular domain, containing a ligand-binding domain, a short transmembrane domain and an intracellular domain containing a protein tyrosine kinase catalytic domain. Binding of specific ligands to the receptors is associated with receptor
GPCR- FGF2 receptors complexes and functional transactivation
Fibroblast growth factor 2 (FGF2) is a key multi-functional neurotrophic factor that regulates vital functions in the CNS, especially brain development, by promoting neuronal growth and morphogenesis, neurogenesis, survival, migration, differentiation (Belluardo et al., 2000, Belluardo et al., 2004, Belluardo et al., 2008, Frinchi et al., 2010, Mudò et al., 2007, Mudò et al., 2009, Palmer et al., 1999, Raballo et al., 2000, Vescovi et al., 1993, Woodbury and Ikezu, 2014)[Vaccarino, F.M 1999 a e
GPCR- PDGF receptors complexes and functional transactivation
PDGF ligands and PDGF receptors (PDGFRα, and PDGFRβ) are key proteins essential for nervous system development and adult neuronal maintenance (Funa and Sasahara, 2014). Binding of a dimerized PDGF-ligand induces receptor dimerization, which induces autophosphorylation of intracellular kinases and activates the downstream signaling molecules, such as PLCγ, PI3K/AKT, Ras, Src and PKC (Shim et al., 2010, Tallquist and Kazlauskas, 2004). PDGFR activation plays an essential role in embryonal and
GPCR-IGF receptors complexes and functional transactivation
Insulin-like Growth Factor-1 (IGF-1) is essential for normal brain development both in the prenatal and in the early post-natal periods, as well as for neuroplasticity and remodeling throughout life (Dupraz et al., 2013, Dyer et al., 2016, Wrigley et al., 2017). IGF-1 triggers autophosphorylation of its receptor (IGF-1R) and activates the PI3 kinase/AKT and MAPK signaling cascade, which in turn mediate the neuroprotective action of IGF-1 (Laviola et al., 2007). IGF-1R has been characterized as
GPCRs-RTKs bidirectional interaction
As stated before, the interplay between GPCRs and RTKs may take place bidirectionally, as demonstrated by the evidence of the involvement of GPCR signaling molecules, such as heterotrimeric G proteins and arrestins, in RTKs signaling (Delcourt et al., 2007a, Pyne and Pyne, 2011). Similarly to RTKs transactivation by GPCRs, two different mechanisms have been involved in this reciprocal transactivation process: the first one is dependent on the synthesis and secretion of a cognate ligand of the
Conclusions
Numerous neurotransmitters and neuropeptides signal through activation of several GPCRs, thanks to which they elicit a wide variety of functions in the CNS, such as modulation of channel activity, synaptic transmission, differentiation, neuronal growth and survival. In addition, GPCRs by forming heteroreceptor complexes may participate to multiple transactivation mechanisms, involving TRKs as well as other GPCRs, thus modulating several activities in the CNS. Indeed, all the collected data in
Conflicts of interest
None.
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