Water-soluble hormones cannot move across the plasma membrane, so they use protein receptors that span the membrane to trigger intracellular signaling pathways. These pathways activate second messengers inside the cell, including cAMP or calcium ions. Many hormones bind to transmembrane G protein-coupled receptors that link to regulatory G proteins. G proteins can then activate enzymes such as adenylyl cyclase or phospholipase C. Adenylyl cyclase converts ATP to cAMP, which can activate protein kinases. Kinases are enzymes that add phosphate groups to other proteins, initiating a phosphorylation cascade. Epinephrine, glucagon, parathyroid hormone, and luteinizing hormone act through cAMP. Phospholipase C breaks down the membrane phospholipid PIP2 into IP3 and DAG. IP3 then moves to the endoplasmic membrane and binds to an IP3-gated calcium channel, causing a release of calcium ions into the cytoplasm. The change in calcium concentration can induce physiological effects such as muscle contraction. Oxytocin and hypothalamic regulatory hormones amplify signals through PIP2 and calcium ions.