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)

Light absorbed by retinal photoreceptors triggers a cascade of reactions that initiate cGMP hydrolysis, cation channel closure and membrane hyperpolarization. Down-regulation of the cascade involves additional proteins that interfere with amplification along the cascade. Pinealocytes are activated by norepinephrine during the dark phase of the day/night cycle. Mature pinealocytes of the mammalian pineal express the known photoreceptor proteins that are implicated in down-regulation of the visual cascade, but the cascade components that produce cGMP hydrolysis and membrane hyperpolarization are absent. Pinealocytes accumulate cyclic AMP minimally when norepinephrine activates their beta adrenergic receptors alone, but the response is potentiated by the simultaneous activation of their alpha-1 adrenergic receptors. A model is proposed whereby phosducin, a phosphoprotein that binds the beta,gamma subunit of G-proteins, could modulate the synthesis of cyclic AMP by buffering the amount of beta,gamma G-protein subunits that are available for activating adenylate cyclase.
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PMID:Photoreceptors of the retina and pinealocytes of the pineal gland share common components of signal transduction. 153 28

Phosducin (Phd), a cytosolic protein, has been proposed to compete with certain receptor kinases for Gbetagamma of heterotrimeric G proteins, and may inhibit GTPase activity of G alpha s. These suggestions together with the enhancing effect of Phd on odorant-induced cAMP accumulation let us assume a stimulatory action of the protein on intracellular signaling. Therefore, this investigation was designed to examine the excitatory effect of PGE1 on signal transmission in neuroblastoma x glioma hybrid cells (NG 108-15) overexpressing Phd. The neuronal cells stably expressing Phd were found to display a 3 to 4-fold increased sensitivity to PGE1 as compared to wild type cells, using cAMP accumulation as measure. Examination of membranes prepared from Phd-overexpressing cells revealed an elevated GTPase activity as indicated by the formation of 32Pi upon PGE1 challenge. This activity was inhibited by exogenous Phd. In addition, receptor independent stimulation of adenylate cyclase by forskolin reveals an increased formation of cAMP in Phd expressing cells, which is accompanied by an increased binding of [3H]forskolin. The findings let us propose that Phd elevates intracellular levels of functional G alpha s which accounts for the increased response to PGE1.
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PMID:Phosducin expression in NG 108-15 hybrid cells enhances prostaglandin E1 stimulated adenylate cyclase activity. 949 6

Over the past 20 years, the general mechanism for signaling through 7-transmembrane helix receptors coupled to GTP hydrolysis has been worked out. Although similar in overall organization, subtype variability and subcellular localization of components have built in considerable signaling specificity. Atomic resolution structures for many of the components have delineated the domain organization of these complex proteins and have given physical form to the idea of subtype specificity. This review describes what is known about the physical structures of the 7-transmembrane helix receptors, the heterotrimeric GTP binding coupling proteins, the adenylate cyclase and phospholipase C effector proteins, and signaling modulatory proteins, such as arrestin, phosducin, recoverin-type myristoyl switch proteins, and the pleckstrin homology domain of G-protein receptor kinase-2. These images allow experimenters to contemplate the details of the supramolecular organization of the multiprotein complexes involved in the transmission of signals across the cellular lipid bilayer.
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PMID:Structural features of heterotrimeric G-protein-coupled receptors and their modulatory proteins. 1037 66

To understand the requirements for binding to G protein betagamma subunits, phage-displayed random peptide libraries were screened using immobilized biotinylated betagamma as the target. Selected peptides were grouped into four different families based on their sequence characteristics. One group (group I) had a clear conserved motif that has significant homology to peptides derived from phospholipase C beta (PLC beta) and to a short motif in phosducin that binds to G protein beta subunits. The other groups had weaker sequence homologies or no homology to the group I sequences. A synthetic peptide from the strongest consensus group blocked activation of PLC by G protein betagamma subunits. The peptide did not block betagamma-mediated inhibition of voltage-gated calcium channels and had little effect on betagamma-mediated inhibition of Gs-stimulated type I adenylate cyclase. Competition experiments indicated that peptides from all four families bound to a single site on betagamma. These peptides may bind to a protein-protein interaction 'hot spot' on the surface of betagamma subunits that is used by a subclass of effectors.
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PMID:Evidence that a protein-protein interaction 'hot spot' on heterotrimeric G protein betagamma subunits is used for recognition of a subclass of effectors. 1117 21