Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:4.6.1.1 (adenylate cyclase)
 19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A variety of neurotransmitters and other chemical substances are released into the extracellular space in the brain in response to acute ischemic stress, and the biological actions of these substances are exclusively mediated by receptor-linked second messenger systems. One of the well-known second messenger systems is adenylate cyclase, which catalyzes the generation of cyclic AMP, triggering the activation of cyclic AMP-dependent protein kinase (PKA). PKA controls a number of cellular functions by phosphorylating many substrates, including an important DNA-binding transcription factor, cyclic AMP response element binding protein (CREB). CREB has recently been shown to play an important role in many physiological and pathological conditions, including synaptic plasticity and neuroprotection against various insults, and to constitute a convergence point for many signaling cascades. The autoradiographic method developed in our laboratory enables us to simultaneously quantify alterations of the second messenger system and local cerebral blood flow (lCBF). Adenylate cyclase is diffusely activated in the initial phase of acute ischemia (< or = 30 min), and its activity gradually decreases in the late phase of ischemia (2-6 h). The areas of reduced adenylate cyclase activity strictly coincide with infarct areas, which later become visible. The binding activity of PKA to cyclic AMP, which reflects the functional integrity of the enzyme, is rapidly suppressed during the initial phase of ischemia in the ischemic core, especially in vulnerable regions, such as the CA1 of the hippocampus, and it continues to decline. By contrast, PKA binding activity remains enhanced in the peri-ischemia area. These changes occur in a clearly lCBF-dependent manner. CREB phosphorylation at a serine residue, Ser(133), which suggests the activation of CREB-mediated transcription of genes containing a CRE motif in the nuclei, remains enhanced in the peri-ischemia area, which is spared of infarct damage. On the other hand, CREB phosphorylation at Ser133 rapidly diminishes in the ischemic core before the histological damage becomes manifest. The Ca2+ influx during membrane depolarization contributes to CREB phosphorylation in the initial phase of post-ischemic recirculation, while PKA activation and other signaling elements seem to be responsible in the later phase. These findings suggest that derangement of cyclic AMP-related intracellular signal transduction closely parallels ischemic neuronal damage and that persistent enhancement of this signaling pathway is important for neuronal survival in acute cerebral ischemia.
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PMID:Alteration of second messengers during acute cerebral ischemia - adenylate cyclase, cyclic AMP-dependent protein kinase, and cyclic AMP response element binding protein. 1140 78

We have examined the possible role of adenosine 3',5'-phosphate (cAMP) in functions associated with the plasma membranes of Saccharomyces cerevisiae. Purified membranes from this source contained an adenylate cyclase which was insensitive to activation by fluoride or guanine nucleotides, only weakly responsive to changes of carbon source in the growth medium, and strongly stimulated by vanadate. They also contained at least two classes of receptor proteins for guanine nucleotides (as measured by binding of labeled 5'-guanylyl methylene diphosphate) with apparent dissociation constants equal to 1.0 x 10(-7) and 3 x 10(-6) M, a protein kinase capable of phosphorylating added histones, the activity of which was stimulated by cAMP, and cAMP receptors that may function as regulatory subunits for this kinase. Membrane proteins were also susceptible to phosphorylation by endogenous kinase(s), with polypeptides of apparent molecular weights equal to 160 x 10(3), 135 x 10(3), 114 x 10(3), and 58 x 10(3) as the major targets. Of these, the 114,000-molecular-weight polypeptide was probably identical to the proton-translocating ATPase of the membranes. However, the cAMP-dependent protein kinase did not appear to be involved in these reactions. Intact (rho+ or rho0) cells responded to dissipation of the proton electrochemical gradient across their plasma membranes by rapid and transient changes in their intracellular level of cAMP, as suggested earlier (J. M. Trevillyan and M. L. Pall, J. Bacteriol., 138:397-403, 1979). Thus, although yeast plasma membranes contain all the essential components of a stimulus-responsive adenylate cyclase system, the precise nature of the coupling device and the targets involved remain to be established.
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PMID:Properties and possible functions of the adenylate cyclase in plasma membranes of Saccharomyces cerevisiae. 1458 90

Incubation with noradrenaline (norepinephrine) of isolated membranes of rat's brain corpus striatum and cortex, showed that ionic-magnesium (Mg(2+)) is required for the neurotransmitter activatory response of adenylate cyclase [ATP pyrophosphate-lyase (cyclizing) (EC 4.6.1.1)], AC. An Mg(2+)-dependent response to the activatory effects of adrenaline, and subsequent inhibition by calcium, suggest capability for a turnover, associated with cyclic changes in membrane potential and participation in a short-term memory pathway. In the cell, the neurotransmitter by activating AC generates intracellular cyclic AMP. Calcium entrance in the cell inhibits the enzyme. The increment of cyclic AMP activates kinase A and their protein phosphorylating activity, allowing a long-term memory pathway. Hence, consolidating neuronal circuits, related to emotional learning and memory affirmation. The activatory effect relates to an enzyme-noradrenaline complex which may participate in the physiology of the fight or flight response, by prolonged exposure. However, the persistence of an unstable enzyme complex turns the enzyme inactive. Effect concordant, with the observation that prolonged exposure to adrenaline, participates in the etiology of stress triggered pathologies. At the cell physiological level AC responsiveness to hormones could be modulated by the concentration of chelating metabolites. These ones produce the release of free ATP(4-), a negative modulator of AC and the Mg(2+) activated insulin receptor tyrosine kinase (IRTK), thus, allowing an integration of the hormonal response of both enzymes by ionic controls. This effect could supersede the metabolic feedback control by energy charge. Accordingly, maximum hormonal response of both enzymes, to high Mg(2+) and low free ATP(4-), allows a correlation with the known effects of low caloric intake increasing average life expectancy.
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PMID:Characterization of the norepinephrine-activation of adenylate cyclase suggests a role in memory affirmation pathways. Overexposure to epinephrine inactivates adenylate cyclase, a causal pathway for stress-pathologies. 2014 84

Our work suggests that heteromer formation, mainly involves linear motifs (LMs) found in disordered regions of proteins. Local disorder imparts plasticity to LMs. Most molecular recognition of proteins occurs between short linear segments, known as LMs. Interaction of short continuous epitopes is not constrained by sequence and has the advantage of resulting in interactions with micromolar affinities which suit transient, reversible complexes such as receptor heteromers. Electrostatic interactions between epitopes of the G-protein coupled receptors (GPCR) involved, are the key step in driving heteromer formation forward. The first step in heteromerization, involves phosphorylating Ser/Thr in an epitope containing a casein kinase 1/2-consensus site. Our data suggest that dopaminergic neurotransmission, through cAMP-dependent protein kinase A (PKA) slows down heteromerization. The negative charge, acquired by the phosphorylation of a Ser/Thr in a PKA consensus site in the Arg-rich epitope, affects the activity of the receptors involved in heteromerization by causing allosteric conformational changes, due to the repulsive effect generated by the negatively charged phosphate. In addition to modulating heteromerization, it affects the stability of the heteromers' interactions and their binding affinity. So here we have an instance where phosphorylation is not just an on/off switch, instead by weakening the noncovalent bond, heteromerization acts like a rheostat that controls the stability of the heteromer through activation or inhibition of adenylate cyclase by the neurotransmitter Dopamine depending on which Dopamine receptor it docks at.
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PMID:How adenylate cyclase choreographs the pas de deux of the receptors heteromerization dance. 2343 92


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