Cyclic adenosine monophosphate binding protein

Figure 1.10 Model of a G protein-coupled receptor with 7 membrane-spanning domains. Binding of an agonist to the receptor causes GDP to exchange with GTP. The a-GTP complex then dissociates from the receptor and the py complex and interacts with intercellular en mes or ion channels. The Py complex can activate an ion channel or possibly also interact with intercellular enzymes. GDP, guanine diphosphate GTP, guanine triphosphate cAMP, cyclic adenosine monophosphate PKC, protein kinase C PLC, phospholipase C DAG, diacylglycerol.

Fig. 4 Assays for G-protein-coupled receptors. The two main ciasses are binding and functional assays. Binding assays detect compounds that are ligands of the receptor. Functional assays probe the signaling of the receptor within the cell. Gs/i and Gq/i, G-proteins PLC, phospholipase C AC, adenylyl cyclase DAG, diacylglycerol cAMP, cyclic adenosine monophosphate PKC, protein kinase C PKA, protein kinase A (PKA) lns(l,4,5)P3, inositol phosphates P-CREB, phosphorylated cAMP response element binding protein CRE, cAMP regulatory element.

In keeping with their proposed cytoskeletal nature, IFPs initially were thought to serve a purely structural role in muscle cells. It was hypothesized that the function of these proteins was to keep other cytoplasmic proteins in proper relationship to one another, as well as to anchor the cytoplasmic contractile apparatus to the cell membrane. Flowever, subsequent developments in cell biology cast considerable doubt on this premise." The intermediate filaments are now known to serve a nucleic acid-binding function moreover, they are susceptible to processing by calcium-activated proteases and are substrates for cyclic adenosine monophosphate-dependent protein kinases. Thus, it has been proposed that all IFPs serve as modulators between extracellular influences governing calcium flux into the cell (and subsequent protease activation) and nuclear function at a transcriptional... 

A sequence stretch 300 base pairs upstream of the transcriptional start site suffices for most of the transcriptional regulation of the IL-6 gene (Fig. 1). Within this sequence stretch several transcription factors find their specific recognition sites. In 5 to 3 direction, AP-1, CREB, C/EBP 3/NF-IL6, SP-1 and NF-kB can bind to the promoter followed by TATA and its TATA binding protein TBP. Most enhancer factors become active in response to one or several different stimuli and the active factors can trigger transcription individually or in concert. For example, AP-1 is active upon cellular stress, or upon stimuli that tell cells to proliferate CREB becomes also active if cells experience growth signals, but also upon elevation of intracellular levels of cyclic adenosine monophosphate (cAMP), which occurs upon stimulation if so called hormone-activated G protein-coupled receptors. 

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... 

Antidepressant treatment has, in recent studies, been shown to upregulate the cyclic adenosine monophosphate (cAMP) response element binding protein (CREB) cascade and expression of BDNF [59]. This upregulation of CREB and BDNF raises the possibility that antidepressant treatment could oppose the cell death pathway, possibly via increased expression of the oncogene Bcl-2. Studies are necessary to determine if antidepressant treatment increases Bcl-2 expression. Increased expression of Bcl-2 in brain and cultured cells, and inhibition of apoptosis of cultured cerebellar granule neurons have been reported with lithium treatment [57]. Mice lacking the BDNF TrkB receptor fail to show behavioral and neurogenic responses to antidepressants. 

The activation of adenylyl cyclase enables it to catalyze the conversion of adenosine triphosphate (ATP) to 3 5 -cyclic adenosine monophosphate (cAMP), which in turn can activate a number of enzymes known as kinases. Each kinase phosphorylates a specific protein or proteins. Such phosphorylation reactions are known to be involved in the opening of some calcium channels as well as in the activation of other enzymes. In this system, the receptor is in the membrane with its binding site on the outer surface. The G protein is totally within the membrane while the adenylyl cyclase is within the membrane but projects into the interior of the cell. The cAMP is generated within the cell (see Rgure 10.4). 

Five subtypes of dopamine receptors have been described they are the Dj-like and Dj-like receptor groups. All have seven transmembrane domains and are G protein-coupled. The Dj-receptor increases cyclic adenosine monophosphate (cAMP) formation by stimulation of dopamine-sensitive adenylyl cyclase it is located mainly in the putamen, nucleus accumbens, and olfactory tubercle. The other member of this family is the D5-receptor, which also increases cAMP but has a 10-fold greater affinity for dopamine and is found primarily in limbic regions. The therapeutic potency of antipsychotic drugs does not correlate with their affinity for binding to the Dj-receptor. 

Uterine relaxation is mediated in part through inhibition of MLCK. This inhibition results from the phosphorylation of MLCK that follows the stimulation of myometrial (3-adrenoceptors relaxation involves the activity of a cyclic adenosine monophosphate (cAMP) mediated protein kinase, accumulation of Ca++ in the sarcoplasmic reticulum, and a decrease in cytoplasmic Ca. Other circulating substances that favor quiescence of uterine smooth muscle include progesterone, which increases throughout pregnancy, and possibly prostacyclin. Progesterone s action probably involves hyperpolarization of the muscle cell membrane, reduction of impulse conduction in muscle cells, and increased calcium binding to the sarcoplasmic reticulum. 

Activation of Gs or Gi proteins results in stimulation or inhibition, respectively, of adenylyl cyclase which catalyses the formation of cyclic adenosine monophosphate (cAMP) from ATP The cAMP binds to protein kinase A (PKA), which mediates the diverse cellular effects of cAMP by phosphorylating substrate enzymes, thereby increasing their activity. Among the responses mediated by cAMP are increases in contraction of cardiac and skeletal muscle and glycogenolysis in the liver by adrenaline (epinephrine). Because a single activated receptor can cause the conversion of up to 100 inactive Gs proteins to the active form, and each of these results in the synthesis of several hundred cAMP molecules, there is a very considerable signal amplification. For example, adrenaline concentrations as low as 10-10 M can stimulate the release of glucose sufficient to increase... 

In close proximity to the parietal cells are gut endocrine cells called enterochromaffin-like (ECL) cells. ECL cells have receptors for gastrin and acetylcholine and are the major source for histamine release. Histamine binds to the H2 receptor on the parietal cell, resulting in activation of adenylyl cyclase, which increases intracellular cyclic adenosine monophosphate (cAMP). cAMP activates protein kinases that stimulate acid secretion by the H+/K+ ATPase. In humans, it is believed that the major effect of gastrin upon acid secretion is mediated indirectly through the release of histamine from ECL cells rather than through direct parietal cell stimulation. 

When the odorant binds to the odorant receptor it changes the receptor structure and activates an olfactory protein called a G protein. This in turn converts ATP (adenosine triphosphate) to cAMP (cyclic adenosine monophosphate) that allows opening of ion channels, causing the receptor to become depolarized. Depolarization is an electrical change that triggers a nerve impulse. Impulses from the nasal receptors are sent along the olfactory nerve to the brain. 

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