Cytoplasmic second messengers

The GABAB-receptors, the muscarinic M2- and IVU-receptors for acetylcholine, the dopamine D2-, D3-and D4-receptors, the a2-adrenoceptors for noradrenaline, the 5-HTiA F-receptors for serotonin, and the opioid p-, 8- and K-receptors couple to G proteins of the Gi/o family and thereby lower [1] the cytoplasmic level of the second messenger cyclic AMP and [2] the open probability ofN- andP/Q-type Ca2+ channels (Table 1). The muscarinic Mr, M3- and M5-receptors for acetylcholine and the ai-adrenoceptors for noradrenaline couple to G proteins of the Gq/11 family and thereby increase the cytoplasmic levels of the second messengers inositol trisphosphate and diacylglycerol (Table 1). The dopamine Dr and D5-receptors and the (3-adrenoceptors for noradrenaline, finally, couple to Gs and thereby increase the cytoplasmic level of cyclic AMP. 

The intracellular hgand-gated Ca " channels include the channels in endoplasmic and sarcoplasmic reticulum (SR) membranes that are opened upon binding of the second messenger, inositol triphosphate (IP3). These are intracellular Ca release channels that allow Ca to exit from intracellular stores, and consequently to increase the concentration of cytoplasmic Ca [5]. A second type of intracellular Ca release channel is the Ca - and ryanodine-sensitive channel that was originally characterized and isolated from cardiac and skeletal muscle [5-7] but appears to exist in many types of cells. It has become evident that IP3-gated channels and ryanodine-sensitive channels are structurally related but distinct proteins [8] that are present in many cell types [9]. While very interesting, time and space will not allow for further discussion of these channels. 

The most common second messenger activated by protein/peptide hormones and catecholamines is cyclic adenosine monophosphate (cAMP). The pathway by which cAMP is formed and alters cellular function is illustrated in Figure 10.1. The process begins when the hormone binds to its receptor. These receptors are quite large and span the plasma membrane. On the cytoplasmic surface of the membrane, the receptor is associated with a G protein that serves as the transducer molecule. In other words, the G protein acts as an intermediary between the receptor and the second messengers that will alter cellular activity. These proteins are referred to as G proteins because they bind with guanosine nucleotides. In an unstimulated cell, the inactive G protein binds guanosine diphosphate (GDP). When the hormone... 

The cAMP molecule serves as the second messenger, which carries out the effects of the hormone inside the cell. The primary function of cAMP is to activate protein kinase A. This kinase then attaches phosphate groups to specific enzymatic proteins in the cytoplasm. The phosphorylation of these enzymes enhances or inhibits their activity, resulting in the enhancement or inhibition of specific cellular reactions and processes. Either way, cellular... 

Water-soluble hormones must transmit signals to affect metabolism and gene ejcpression without themselves entering the cytoplasm. They often do so via second messenger systems that, in turn, activate protein kinases. 

Insulin binding activates the tyrosine kinase activity associated with the cytoplasmic domain of its receptor as shown in F jure 1-9-4. There is no trimeric G protein, enzyme, or second messenger required to activate this protein tyrosine kinase activity ... 

In cells that use Ca + as second messenger, binding of an external signal to a cell membrane receptor activates phospholipase C (PLC), which, in turn, synthesizes inositol 1,4,5-trisphosphate (InsP3). This metabolite binds to an InsP3 receptor located on the membrane of internal Ca + stores (endoplasmic or sarcoplasmic reticulum) and thereby triggers the release of Ca " " into the cytoplasm of the cell [56]. A conspicuous feature of Ca release is that it is self-amplified Cytosohc Ca + triggers the release of Ca " " from intracellular stores into the cytosol, a process known as Ca +-induced Ca " " release (CICR) [57, 58]. 

Specific signals (e.g., an action potential or second messenger such as insPs or cAMP) can trigger a sudden increase in the cytoplasmic Ca "" level to 500-1000 nM by opening Ca "" channels in the plasma membrane or in the membranes of the endoplasmic or sarcoplasmic reticulum. Ryanodine, a plant substance, acts in this way on a specific channel in the ER. in the cytoplasm, the Ca "" level always only rises very briefly (Ca "" spikes ), as prolonged high concentrations in the cytoplasm have cytotoxic effects. 

Receptor desensitization may also be mediated by second-messenger feedback. For example, adrenoceptors stimulate cAMP accumulation, which leads to activation of protein kinase A protein kinase A can phosphorylate residues on receptors, resulting in inhibition of receptor function. For the B2 receptor, phosphorylation occurs on serine residues both in the third cytoplasmic loop and in the carboxyl terminal tail of the receptor. Similarly, activation of protein kinase C by Gq-coupled receptors may lead to phosphorylation of this class of G protein-coupled receptors. This second-messenger feedback mechanism has been termed heterologous desensitization because activated protein kinase A or protein kinase C may phosphorylate any structurally similar receptor with the appropriate consensus sites for phosphorylation by these enzymes. 

The adenylate cyclases (AC) are a family of enzymes, which catalyze the synthesis of cyclic AMP (cAMP), from ATP. Cyclic AMP, a ubiquitous molecule in mammalian cells, plays a key role in controlling a vast number of biological processes, functioning as a major second messenger. The ACs are present in bacteria, where c-AMP plays a key role in the regulation of transcription in fungi, parasites and mammalian cells. The mammalians ACs (at least nine enzymes) are structurally unrelated to the bacterial ones consisting of 12 transmembrane helices and two cytoplasmic catalytic domains. They differ from each other in their... 

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