GPCR Signal Transduction: Evolution by Gene Duplication


Signal transduction cascades initiated by G‐protein‐coupled receptors (GPCRs) integrate a number of components including seven‐pass transmembrane receptors (7TM), heterotrimeric G‐proteins, downstream protein kinases and responsive transcription factors. This signalling pathway has evolved to facilitate a number of cellular responses related to metabolism, cell proliferation, neurotransmission, DNA repair and many other critical processes. Gene duplication and subfunctionalisation events have contributed to the emergence of several core components of the GPCR signalling pathway over the course of eukaryotic evolutionary history. Four key components of this pathway include GPCRs, receptor‐associated heterotrimeric G‐proteins, downstream kinase targets, such as protein kinase A (PKA) and transcription factors such as cAMP response element binding protein (CREB).

Key Concepts

  • G‐protein‐coupled receptors (GPCRs) are seven‐pass transmembrane proteins, which have diversified into five main families over evolutionary time.
  • Heterotrimeric G‐proteins transduce nuanced responses via different combinations of α, β and γ‐subunits, which have evolved from numerous well‐defined duplication events.
  • Protein kinase A (PKA) is a downstream hub whose catalytic and regulatory subunits have diversified in eukaryotic lineages.
  • The cAMP response element‐binding protein (CREB) function is highly conserved in eukaryotes while the auxiliary components of its pathway have changed.

Keywords: gene duplication; molecular evolution; G‐protein‐coupled receptor (GPCR); heterotrimeric G‐proteins; A‐kinase binding protein (AKAP); protein kinase A (PKA); cAMP response element‐binding protein (CREB)

Figure 1. Schematic of one possible GPCR transduction pathway. The ligand‐bound GPCR (1) acts as a guanine–nucleotide exchange factor (GEF) for the Gα subunit of a Gs heterotrimeric G‐protein (2). Once bound to GTP, Gα dissociates from Gβγ and binds adenylate cyclase, which results in increased intracellular cAMP (3). Binding of cAMP to PKA‐R (4) induces a conformational change, which activates the catalytic activity of PKA‐C (5). Targets of PKA such as CREB are subsequently phosphorylated (6) and activated. CREB is a transcription factor localised primarily not only to the nucleus but also to the cytosol and mitochondria. CREB activation (7) results in altered gene expression.
Figure 2. Phylogeny of representative eukaryotic PKA catalytic subunits. The duplication event responsible for the emergence of α and β catalytic subunits (encoded for by PRKACA and PRKACB) occurred following the divergence of the genus Arthropoda (represented here by D. melanogaster). Protein sequences and corresponding mRNA sequences were obtained from RefSeq Protein and RefSeq Nucleotide, respectively. Homology was inferred via BLAST similarity search using BLOSUM45 and expectation value threshold E < 10−7. This tree represents the consensus of protein distance, protein maximum‐likelihood, DNA distance, DNA maximum‐likelihood and DNA parsimony trees. Rooting of this tree was accomplished using the eukaryotic green microalga A. protothecoides as an outgroup.
Figure 3. Consensus logo for human CREB binding sites (E < 3.8 x 10–125). This palindromic binding site has the consensus sequence 5′‐TGACGTCA‐3′ with half‐sites 5′‐TGACG‐3′and 5′‐CGTCA‐3′. The logo presented here was generated using sequence data contained in Genome Reference Consortium Human Build 37 (GRCh37) which was accessed via the UCSC Genome Browser. CREB binding sites within the genome were identified using chromatin immunoprecipitation (ChIP‐Seq) data obtained from the Encyclopedia of DNA Elements (ENCODE). CREB binding sites located between 1000 nucleotides upstream of transcription start sites (TSS) and 500 nucleotides downstream of TSS were aligned. The consensus sequence was generated from this alignment using the MEME suite (Bailey et al., ).


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McMullen, Timothy P, Brown, Evan A, Ausrafuggaman, Nahid, Sahu, Alisha, Güler, Ali D, and Deppmann, Christopher D(Sep 2018) GPCR Signal Transduction: Evolution by Gene Duplication. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0028190]