High resolution

Module 2: Figure cyclic AMP signalling

Organization and function of the cyclic AMP signalling pathway.

Cyclic AMP is formed both by membrane-bound adenylyl cyclase and by the bicarbonate-sensitive soluble adenylyl cyclase. The former is regulated by both stimulatory agonists that act through the αS subunit or through inhibitory agonists that act through either the αi or the βγ subunits. The increase in cyclic AMP then acts through three different effector systems. It acts through the exchange protein activated by cyclic AMP (EPAC), which functions to activate Rap1. It can open cyclic nucleotide-gated channels (CNGCs). The main action of cyclic AMP is to activate protein kinase A (PKA) to phosphorylate a large number of downstream targets. Some of these drive specific processes such as gene transcription through phosphorylation of cyclic AMP response element-binding protein (CREB), and activation of ion channels [e.g. AMPA receptors and cystic fibrosis transmembrane conductance regulator (CFTR)] and various enzymes that control metabolism [e.g. fructose 2,6-bisphosphate (F-2,6-P2) 2-phosphatase, lipase and phosphorylase kinase]. Other downstream targets are components of other signalling pathways such as the cyclic GMP phosphodiesterase (cGMP PDE), the phospholamban (PLN) that controls the sarco/endo-plasmic reticulum Ca2+-ATPase (SERCA), the ryanodine receptor (RYR) and the Ca2+ channels CaV1.1 and CaV1.2.