Regulation of ACs by Ca2+. Ca2+ can directly, and indirectly regulate the nine membrane-bound ACs. Submicromolar [Ca2+] can directly regulate AC, and some ACs specifically respond to Ca2+ derived from capacitative Ca2+ entry (CCE) from store-operated Ca2+ channels (SOCCs). Ca2+ can also regulate AC by binding calmodulin (CaM), and the Ca2+/CaM complex can then affect AC activity. Ca2+-bound CaM can also activate Ca2+/calmodulin-activated kinase (CaMK) and calcineurin (CaN), both of which may regulate AC. More indirectly, Gβγ subunits from Gαq linked receptors can also regulate AC activity. In addition, Gαq can activate phospholipase C (PLC), which converts phosphatidylinositol 4,5-bisphosphate (PIP2) to diacylglycerol (DAG) and inositol trisphosphate (IP3). DAG activates protein kinase C (PKC), which can also modulate the activity of AC; InsP3 binds to and activates its receptors (InsP3R) on the endoplasmic reticulum (ER), thereby releasing Ca2+ from the ER stores into the cytoplasm. This emptying of the ER Ca2+ stores triggers extracellular Ca2+ entry by SOCCs.