Phospholipase G-proteins

MS Baida, GL Mariscal, RG Contreras, MM Silva, TME Marquez, GJA Sainz, M Cereijido. (1991). Assembly and sealing of tight junctions Possible participation of G-proteins, phospholipase C, protein kinase C, and calmodulin. J Membr Biol 122 193-202. 

Voltage-dependent Na+, K+, Ca2+ channels Ca2+-dependent potassium channels Enzymes and other proteins involved in the regulation of second messengers G proteins Phospholipases Adenylyl cyclases Guanylyl cyclases Phosphodiesterases IP3 receptor Protein kinases... 

It is fitting to introduce the phospholipase pathways here because they are controlled by small G proteins. Phospholipases C and D (PLC, PLD) are controlled by Rho/Arf and Cdc42 and Src tyrosine kinases participate in the control of PLD. 36 Phospholipases form potent second messengers, such as inositol trisphosphate (IP3) and diacylglycerol (DAG). In Fig. 4.6a the reactions catalysed by phospholipases C and D and the connections between phospholipases C and D are summarized, and in Fig. 4.6b the regulatory pathways that activate phospholipase D synergistically are summarized.37... 

The binding of many different hormones, ncumtransmil-ters. and growth factors to the cell surface results in activation of the polyphosphoinositide receptor. system.Binding to the specific receptor activates the enzyme phospholipase C through the intermediacy of a G protein. Phospholipase C converts pho.sphatidylinositol 4 5-bisphosphatc (PIP-) into IP3 and DAG. IPj releases calcium ion. which in turn all ccls many cellular responses in the target eells. 

In the PIP2-Ca signal transduction system, the signal is transferred from the epinephrine receptor to membrane-bound phospholipase C by G proteins. Phospholipase C hydrolyzes PIP2 to form diacylglycerol (DAG) and inositol trisphos-phate (IP3). IP3 stimulates the release of Ca from the endoplasmic reticulum. Ca and DAG activate protein kinase C. The amount of calcium bound to one of the calcium-binding proteins, calmodulin, is also increased. 

FIGURE 24.12 The PIP2 second-messenger scheme. When a hormone binds to a receptor, it activates phospholipase C, in a process mediated by a G protein. Phospholipase C hydrolyzes PIPj to IP3 and DAG. IP3 stimulates the release of Ca from intracellular reservoirs in the ER. A complex formed between Ca and the calcium-binding protein calmodulin activates a cytosolic protein kinase for phosphorylation of a target enzyme. DAG remains bound to the plasma membrane, where it activates the membrane-bound protein kinase C (PKC). PKC is involved in the phosphorylation-channel proteins that control the flow of Ca + in and out of the cell. Ca from extracellular sources can produce sustained responses even when the supply of Ca + in intracellular reservoirs is exhausted. 

Finally, both cloned [alpha(lG), alpha(lH) and alpha(ll) subunits] and native T-type Ca + chaimels are blocked by AEA at submicromolar concentrations, independently from the activation of CBj/CBj receptors, G-proteins, phospholipases, and protein kinase (PK) pathways. Block of AEA transport into cells via the AEA membrane transporter (AMT) prevented T-current inhibition, snggesting that AEA acts at an intracellular site (Chemin et al., 2001). 

Two AR subtypes, Ax and A3, couple through G to inhibit adenylate cyclase, while the other two subtypes, A2a and A2B, stimulate adenylate cyclase through Gs or G0if (for A2a). The A2BAR is also coupled to the activation of PLC through Gq. Furthermore, each of these receptors may couple through the (3,y subunits of the G proteins to other effector systems, including ion channels and phospholipases. Levels of intracellular... 

Figure 10. The G-protein cascades in smooth muscle catalyze the exchange GDP for GTP on G-protein. Following the binding of GTP, the trimeric G-protein splits into an a-GTP part and a P-y part. The a-GTP part ordinarily then combines with its specific apoenzyme to constitute the active enzyme. For the activation of the contractile activation path, the enzyme is phospholipase C and the second messenger products are IP3 and DAG. The IP3 in the myoplasm binds to Ca channels in the SR membrane, opening them. Other second messengers include the inhibitors of contractile activity, cGMP and cAMP.

Ca may activate phospholipase A2 and cause production of lyso-lipids and fatty acids. In addition, ionic fluxes across the membrane occur, leading to pH changes and membrane depolarization. It is not clear how these other responses are initiated, but there may be direct G-protein links to effector systems such as phospholipase A2 or ionic channels. 

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