G-protein coupled receptors (GPCRs) are a large and highly important class of membrane proteins, allowing the transduction of an extracellular ligand to an intracellular response, involved in vision (opsins) and hormonal responses. In a GPCR-mediated signalling pathway, the first stage is ligand binding. The binding site for the ligand is typically well within the protein, within a specific binding pocket. It is uncommon for the ligand to bind close to the surface / extracellularly. On ligand binding, the GPCR undergoes a conformational change, activating the $$\text{G}_{\alpha;\text{S}}$$ subunit. This subunit activates adenylyl cyclase, while remaining attached to the bilayer (to prevent loss in the cytoplasm). Adenylyl cyclase catalyses the conversion of ATP to cAMP (a second messenger) and diphosphate. cAMP is a commonly used signalling molecule, and the activation of multiple G-proteins, and the production of many cAMP molecules leads to an amplification of signalling. This can give an outsized effect from a low concentration of signalling molecule, giving a greater response. cAMP activates protein kinase A (PKA), which enters the nucleus (via a nuclear pore), activating CREB (cAMP Response-Element Binding Protein). Activated and phosphorylated CREB binds to the DNA with a CREB Binding Protein (CREB-CBP), activating and upregulating the transcription of the target genes.