When GPCRs bind ligands such as glucagon or epinephrine , the stimulatory G proteins get activated and, in turn, activate the membrane-bound enzyme adenylyl cyclase. The activated enzyme converts ATP to a second messenger cyclic AMP that uses downstream kinases such as protein kinase A or PKA to regulate the metabolism of fats and sugars. Prolonged exposure to a high concentration of ligands induces GPCR phosphorylation by PKA. Receptor phosphorylation blocks the binding of additional Gs and inhibits adenylyl cyclase activation, preventing GPCR overstimulation. Binding of hormones such as prostaglandin E1 or adenosine to GPCRs activates inhibitory G proteins. The activated Gɑi dissociates from GPCR, binds, and inhibits adenylyl cyclase, preventing cyclic AMP synthesis.