Reinventing the Wheel of Cyclic AMP

Chin, Khew‐Voon; Yang, Weng Lang; Ravatn, Roald; Kita, Toru; Reitman, Elena; Vettori, David; Cvijic, Mary Ellen; Shin, Michael J.; Iacono, Lisa

doi:10.1111/j.1749-6632.2002.tb04326.x

Cited by 119 publications

(69 citation statements)

References 90 publications

(118 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The extension of this observation to both human erythroleukemia cells (HEL) and primary macrophages derived from bone marrow demonstrate that this regulation is a conserved signaling motif utilized by several hematopoietic lineages. We further show that regulation of AC7 activity is mediated by the ␣ subunit of G 13 and both G␣ 12 and G␣ 13 are capable of mediating the synergistic effect on AC7 activity. However, the constitutively active proteins, G␣ 13 QL or G␣ 12 QL, act as dominant negative proteins with respect to cAMP regulation.…”

mentioning

confidence: 59%

“…We further show that regulation of AC7 activity is mediated by the ␣ subunit of G 13 and both G␣ 12 and G␣ 13 are capable of mediating the synergistic effect on AC7 activity. However, the constitutively active proteins, G␣ 13 QL or G␣ 12 QL, act as dominant negative proteins with respect to cAMP regulation. These results suggest that AC7 may be a direct or indirect downstream effector of the G 12/13 pathway.…”

mentioning

confidence: 95%

“…In the latter study, a genetically engineered BRET sensor for cAMP, CAMYEL, was used to measure transient changes in intracellular cAMP in real time and in greater detail in living cells. It was shown that activation of the G 13 pathway greatly enhanced G s -stimulated cAMP responses in murine macrophage cells and that this synergistic interaction was transient and occurred at the level of cAMP synthesis, not its degradation.…”

mentioning

confidence: 99%

“…Synthesis of cAMP by membrane-bound AC is primarily regulated by the heterotrimeric G s protein and its modulation by ligand binding to G-protein-coupled receptors (12,13). There are nine membrane-bound mammalian ACs that can be divided into four subgroups based on their sequence similarities and regulatory properties (11,14,15).…”

mentioning

confidence: 99%

See 3 more Smart Citations

Regulation of cAMP Responses by the G12/13 Pathway Converges on Adenylyl Cyclase VII

Jiang

Collins

Davis

et al. 2008

Journal of Biological Chemistry

View full text Add to dashboard Cite

Regulation of intracellular cAMP by multiple pathways enables differential function of this ubiquitous second messenger in a context-dependent manner. Modulation of G s -stimulated intracellular cAMP has long been known to be modulated by the G i and G q /Ca 2؉ pathways. Recently, the G 13 pathway was also shown to facilitate cAMP responses in murine macrophage cells. We report here that this synergistic regulation of cAMP synthesis by the G s and G 13 pathways is mediated by a specific isoform of adenylyl cyclase, AC7. Furthermore, this signaling paradigm exists in several hematopoietic lineages and can be recapitulated by exogenous expression of AC7 in HEK 293 cells. Mechanistic characterization of this synergistic interaction indicates that it occurs downstream of receptor activation and it can be mediated by the ␣ subunit of either G 12 or G 13 . Our results demonstrate that AC7 is a specific downstream effector of the G 12/13 pathway.

show abstract

mentioning

confidence: 59%

mentioning

confidence: 95%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

Regulation of cAMP Responses by the G12/13 Pathway Converges on Adenylyl Cyclase VII

Jiang

Collins

Davis

et al. 2008

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…The second messengers, cAMP and cGMP, mediate the response of cells to a wide variety of hormones and neurotransmitters and modulate many metabolic processes such as cardiac and smooth muscle contraction, glycogenolysis, platelet aggregation, secretion, lipolysis, ion channel conductance, apoptosis, and growth control (1)(2)(3)(4)(5)(6).…”

mentioning

confidence: 99%

Crystal Structures of Phosphodiesterases 4 and 5 in Complex with Inhibitor 3-Isobutyl-1-methylxanthine Suggest a Conformation Determinant of Inhibitor Selectivity

Huai

Liu

Francis

et al. 2004

Journal of Biological Chemistry

121

162

View full text Add to dashboard Cite

Cyclic nucleotide phosphodiesterases (PDEs) are a superfamily of enzymes controlling cellular concentrations of the second messengers cAMP and cGMP. Crystal structures of the catalytic domains of cGMP-specific PDE5A1 and cAMP-specific PDE4D2 in complex with the nonselective inhibitor 3-isobutyl-1-methylxanthine have been determined at medium resolution. The catalytic domain of PDE5A1 has the same topological folding as that of PDE4D2, but three regions show different tertiary structures, including residues 79 -113, 208 -224 (H-loop), and 341-364 (M-loop) in PDE4D2 or 535-566, 661-676, and 787-812 in PDE5A1, respectively. Because H-and M-loops are involved in binding of the selective inhibitors, the different conformations of the loops, thus the distinct shapes of the active sites, will be a determinant of inhibitor selectivity in PDEs. IBMX binds to a subpocket that comprises key residues Ile-336, Phe-340, Gln-369, and Phe-372 of PDE4D2 or Val-782, Phe-786, Gln-817, and Phe-820 of PDE5A1. This subpocket may be a common site for binding nonselective inhibitors of PDEs.Cyclic nucleotide phosphodiesterases (PDEs) 1 hydrolyze cAMP and cGMP to 5Ј-AMP and 5Ј-GMP. The second messengers, cAMP and cGMP, mediate the response of cells to a wide variety of hormones and neurotransmitters and modulate many metabolic processes such as cardiac and smooth muscle contraction, glycogenolysis, platelet aggregation, secretion, lipolysis, ion channel conductance, apoptosis, and growth control (1-6).The human genome encodes 21 PDE genes and over 60 PDE isoforms categorized into 11 families (7-16). PDE molecules contain three regions: an N-terminal splicing region, a regulatory domain, and a catalytic domain near the C terminus. The 11 PDE families share a conserved catalytic domain of about 300 amino acids but rare homology in other regions across families. The function of the N-terminal splicing region of the PDE families is unknown. The regulatory domains of PDEs contain various structural motifs such as a calmodulin-binding domain in PDE1, upstream conserved region in PDE4, PAS (period clock protein, aryl hydrocarbon receptor nuclear translocator, and single-minded protein) domain in PDE8, GAF (cGMP-specific PDE, adenylyl cyclase, and Fh1A) domain in PDE2, -5, -6, -10, and -11. The regulatory domains have been shown to play roles in the regulation of the catalytic activity of PDEs or to participate in cross-talk with other signaling pathways (16 -18).PDEs share high degree (25-49%) of amino acid conservation in the catalytic domains, implying a similar three-dimensional structure of the catalytic domains. However, PDE families and isoforms within the respective family have varying substrate preferences for cAMP and cGMP. The PDE4, -7, and -8 families prefer to hydrolyze cAMP, whereas PDE5, -6, and -9 are cGMP-specific. PDE1, -2, -3, -10, and -11 show activities toward both substrates but have distinct K m values for cAMP and cGMP (16). In addition, many PDE families possess selective inhibitors that bind to the conserved active sit...

show abstract

Synaptic Transmission: Intracellular Signaling

Free

Hazelwood

Namkung

et al. 2007

Handbook of Contemporary Neuropharmacology

View full text Add to dashboard Cite

In synaptic signaling, the response of an individual neuron is determined by its complement of receptors. As discussed in other chapters in this volume, ligand‐gated ion channels mediate fast synaptic transmission between neurons. However, signaling within an individual neuron is mediated by a complex set of interactions that occur primarily as a result of G protein linked signal transduction. The beauty of this system is in its diversity and inherent capacity for amplification and plasticity in the modulation of many different cellular functions. The initial signal sequence in this type of signaling typically is the generation of a second messenger inside the cell that then in turn activates a number of different proteins capable of modifying cellular processes. This chapter will present examples and an in depth discussion of these intracellular signaling pathways beginning with G protein linked signaling, perpetuated by G protein coupled receptor (GPCR) stimulation. Next, ion channel modulation via G proteins as well as direct GPCR interactions with the channels will be discussed. The long list of intracellular downstream effector pathways including cyclic nucleotide signaling, protein kinase signaling and calcium regulated signaling are also described. The final focus of the chapter is protein phosphorylation cascades, a predominant mechanism in many signal transduction schemes. It is through these complex interactions that an individual cell is able to respond to neurotransmitter stimulation and modify many of its cellular processes to contribute to the overall symphony of synaptic signaling.

show abstract

Reinventing the Wheel of Cyclic AMP

Cited by 119 publications

References 90 publications

Regulation of cAMP Responses by the G12/13 Pathway Converges on Adenylyl Cyclase VII

Regulation of cAMP Responses by the G12/13 Pathway Converges on Adenylyl Cyclase VII

Crystal Structures of Phosphodiesterases 4 and 5 in Complex with Inhibitor 3-Isobutyl-1-methylxanthine Suggest a Conformation Determinant of Inhibitor Selectivity

Synaptic Transmission: Intracellular Signaling

Contact Info

Product

Resources

About