Class III adenylyl cyclases: molecular mechanisms of catalysis and regulation

Linder, Jürgen

doi:10.1007/s00018-006-6072-0

Cited by 92 publications

(102 citation statements)

References 136 publications

(182 reference statements)

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“…food odors (Mansourian and Stensmyr, 2015 ] i ) affects the activity of some isoforms of the eukaryotic class III ACs (Linder, 2006), stimuli consisting of 100 µmol l −1 ethyl hexanoate, VUAA1 or forskolin solutions were delivered in regular Ringer solution (containing both Ca 2+ and Na + ) or in Ca 2+ /Na + -free Ringer solution in order to prevent extracellular /Na + -free Ringer solution (E,F), or expressing a mutated Or22a (Or22a…”

Section: Resultsmentioning

confidence: 99%

Odor induced cAMP production in Drosophila melanogaster olfactory sensory neurons

Miazzi

Hansson

Wicher

2016

Journal of Experimental Biology

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Insect odorant receptors are seven transmembrane domain proteins that form cation channels, whose functional properties such as receptor sensitivity are subject to regulation by intracellular signaling cascades. Here, we used the cAMP fluorescent indicator Epac1-camps to investigate the occurrence of odor-induced cAMP production in olfactory sensory neurons (OSNs) of Drosophila melanogaster. We show that stimulation of the receptor complex with an odor mixture or with the synthetic agonist VUAA1 induces a cAMP response. Moreover, we show that while the intracellular Ca 2+ concentration influences cAMP production, the OSN-specific receptor OrX is necessary to elicit cAMP responses in Ca 2+ -free conditions. These results provide direct evidence of a relationship between odorant receptor stimulation and cAMP production in olfactory sensory neurons in the fruit fly antenna and show that this method can be used to further investigate the role that this second messenger plays in insect olfaction.

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Section: Resultsmentioning

confidence: 99%

Odor induced cAMP production in Drosophila melanogaster olfactory sensory neurons

Miazzi

Hansson

Wicher

2016

Journal of Experimental Biology

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“…AC1 is stimulated synergistically by G␣s and Ca 2ϩ /calmodulin, and inhibited by calmodulin kinase IV, Gi, Go, and Gz (17). AC2 is activated by PKC and G␣s, with conditional stimulation by G␤␥ (17). AC3 is typically considered the olfactory cyclase with stimulation by G␣s and inhibition by calmodulin kinase II and RGS2 (18).…”

Section: Discussionmentioning

confidence: 99%

The A-kinase anchoring protein Yotiao binds and regulates adenylyl cyclase in brain

Piggott

Bauman

Scott

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

132

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A-kinase anchoring proteins (AKAPs) influence the spatial and temporal regulation of cAMP signaling events. Anchoring of PKA in proximity to certain adenylyl cyclase (AC) isoforms is thought to enhance the phosphorylation dependent termination of cAMP synthesis. Using a combination of immunoprecipitation and enzymological approaches, we show that the plasma membrane targeted anchoring protein AKAP9/Yotiao displays unique specificity for interaction and the regulation of a variety of AC isoforms. Yotiao inhibits AC 2 and 3, but has no effect on AC 1 or 9, serving purely as a scaffold for these latter isoforms. Thus, Yotiao represents an inhibitor of AC2. The N terminus of AC2 (AC2-NT), which binds directly to amino acids 808 -957 of Yotiao, mediates this interaction. Additionally, AC2-NT and Yotiao (808 -957) are able to effectively inhibit the association of AC2 with Yotiao and, thus, reverse the inhibition of AC2 by Yotiao in membranes. Finally, disruption of Yotiao-AC interactions gives rise to a 40% increase in brain AC activity, indicating that this anchoring protein functions to directly regulate cAMP production in the brain. 2). This family of proteins functions to target PKA and other cAMP effector proteins to specific regions of the cell allowing for increased signaling specificity. Several members of this diverse protein family bind other receptors, channels, or enzymes to form tightly regulated signaling modules, facilitating PKA interactions with its downstream effectors. In addition, these signaling modules often constitute feedback loops between kinases and phosphatases or recruit phosphodiesterases to terminate the cAMP signal (3).Our labs previously identified a complex containing AKAP79/ 150 and type 5 adenylyl cyclase (AC), that facilitates the spatiotemporal organization of cAMP signaling (4). AKAP79 inhibits AC5 activity, while providing a mechanism for feedback inhibition via PKA phosphorylation of anchored AC5. However, with Ϸ30 gene families of AKAPs identified thus far, and nine mammalian isoforms of AC, it begs the question, does AKAP scaffolding of AC and PKA represent a general paradigm for cAMP signaling? The AKAP Yotiao represents an ideal test case to begin to address this question. Yotiao is a splice variant of the AKAP9 gene and is present on the plasma membrane (5, 6). In addition to PKA, Yotiao binds protein phosphatase 1 (PP1), NMDA receptors, the heart potassium channel subunit KCNQ1, and the IP 3 R1 (5, 7-9). Interestingly, AKAP anchored PKA phosphorylation of the NMDA receptor, KCNQ1, and IP 3 R1 is necessary for each effector's normal function (8-11). For example, disruption of the KCNQ1 association with Yotiao gives rise to long QT syndrome, a type of heart arrhythmia that can be fatal (12). The requirement for a tight coupling between PKA and KCNQ1, and other effectors suggests that cAMP production must also be tightly regulated, perhaps as even part of this complex.We now show that Yotiao is associated with brain and heart adenylyl cyclases. Yotiao displays specificity am...

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“…CyaB1 protein (27) (Fig. 1), which, like all bacterial type III ACs, works as a homodimer (28,29). We chose to make IlaCs because cAMP is an important second messenger involved in regulation of diverse biological processes (28,29).…”

Section: Significancementioning

confidence: 99%

“…1), which, like all bacterial type III ACs, works as a homodimer (28,29). We chose to make IlaCs because cAMP is an important second messenger involved in regulation of diverse biological processes (28,29). The ability to manipulate cAMP levels in specific cells or tissues in live animals is of significant interest in biomedical research.…”

Section: Significancementioning

confidence: 99%

Engineering adenylate cyclases regulated by near-infrared window light

Ryu

Kang

Nelson

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

105

114

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Bacteriophytochromes sense light in the near-infrared window, the spectral region where absorption by mammalian tissues is minimal, and their chromophore, biliverdin IXα, is naturally present in animal cells. These properties make bacteriophytochromes particularly attractive for optogenetic applications. However, the lack of understanding of how light-induced conformational changes control output activities has hindered engineering of bacteriophytochromebased optogenetic tools. Many bacteriophytochromes function as homodimeric enzymes, in which light-induced conformational changes are transferred via α-helical linkers to the rigid output domains. We hypothesized that heterologous output domains requiring homodimerization can be fused to the photosensory modules of bacteriophytochromes to generate light-activated fusions. Here, we tested this hypothesis by engineering adenylate cyclases regulated by light in the near-infrared spectral window using the photosensory module of the Rhodobacter sphaeroides bacteriophytochrome BphG1 and the adenylate cyclase domain from Nostoc sp. CyaB1. We engineered several light-activated fusion proteins that differed from each other by approximately one or two α-helical turns, suggesting that positioning of the output domains in the same phase of the helix is important for light-dependent activity. Extensive mutagenesis of one of these fusions resulted in an adenylate cyclase with a sixfold photodynamic range. Additional mutagenesis produced an enzyme with a more stable photoactivated state. When expressed in cholinergic neurons in Caenorhabditis elegans, the engineered adenylate cyclase affected worm behavior in a light-dependent manner. The insights derived from this study can be applied to the engineering of other homodimeric bacteriophytochromes, which will further expand the optogenetic toolset.phytochrome | protein engineering | adenylyl cyclase | cAMP | locomotion

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Class III adenylyl cyclases: molecular mechanisms of catalysis and regulation

Cited by 92 publications

References 136 publications

Odor induced cAMP production in Drosophila melanogaster olfactory sensory neurons

Odor induced cAMP production in Drosophila melanogaster olfactory sensory neurons

The A-kinase anchoring protein Yotiao binds and regulates adenylyl cyclase in brain

Engineering adenylate cyclases regulated by near-infrared window light

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