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.
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