<P> These signals then can be terminated by cAMP phosphodiesterase, which is an enzyme that degrades cAMP to 5' - AMP and inactivates protein kinase A . </P> <P> In the phosphatidylinositol signal pathway, the extracellular signal molecule binds with the G - protein receptor (G) on the cell surface and activates phospholipase C, which is located on the plasma membrane . The lipase hydrolyzes phosphatidylinositol 4, 5 - bisphosphate (PIP2) into two second messengers: inositol 1, 4, 5 - trisphosphate (IP3) and diacylglycerol (DAG). IP3 binds with the IP3 receptor in the membrane of the smooth endoplasmic reticulum and mitochondria to open Ca channels . DAG helps activate protein kinase C (PKC), which phosphorylates many other proteins, changing their catalytic activities, leading to cellular responses . </P> <P> The effects of Ca are also remarkable: it cooperates with DAG in activating PKC and can activate the CaM kinase pathway, in which calcium - modulated protein calmodulin (CaM) binds Ca, undergoes a change in conformation, and activates CaM kinase II, which has unique ability to increase its binding affinity to CaM by autophosphorylation, making CaM unavailable for the activation of other enzymes . The kinase then phosphorylates target enzymes, regulating their activities . The two signal pathways are connected together by Ca - CaM, which is also a regulatory subunit of adenylyl cyclase and phosphodiesterase in the cAMP signal pathway . </P> <P> GPCRs become desensitized when exposed to their ligand for a long period of time . There are two recognized forms of desensitization: 1) homologous desensitization, in which the activated GPCR is downregulated; and 2) heterologous desensitization, wherein the activated GPCR causes downregulation of a different GPCR . The key reaction of this downregulation is the phosphorylation of the intracellular (or cytoplasmic) receptor domain by protein kinases . </P>

The advantages of targeted protein degradation over inhibition