Photoactivated adenylyl cyclase

Photoactivated adenylyl cyclase (PAC) is a protein consisting of an adenylyl cyclase enzyme domain directly linked to a BLUF (blue light receptor using FAD) type light sensor domain. When illuminated with blue light, the enzyme domain becomes active and converts ATP to cAMP, an important second messenger in many cells. In the unicellular flagellate Euglena gracilis, PACα and PACβ (euPACs) serve as a photoreceptor complex that senses light for photophobic responses and phototaxis.[2] Small but potent PACs were identified in the genome of the bacteria Beggiatoa (bPAC) and Oscillatoria acuminata (OaPAC).[3][1] While natural bPAC has some enzymatic activity in the absence of light, variants with no dark activity have been engineered (PACmn).[4]

Structure of the photoactivated adenylyl cyclase OaPAC forming a homodimer. FMN: flavin mononucleotide, the light-absorbing pigment. [1]

Use of PACs as optogenetic tools

As PACs consist of a light sensor and an enzyme in a single protein, they can be expressed in other species and cell types to manipulate cAMP levels with light. When bPAC is expressed in mouse sperm, blue light illumination speeds up the swimming of transgenic sperm cells and aids fertilization.[5] When expressed in neurons, illumination changes the branching pattern of growing axons.[6] PAC has been used in mice to clarify the function of neurons in the hypothalamus, which use cAMP signaling to control mating behavior.[7] Expression of PAC together with K+-specific cyclic-nucleotide-gated ion channels (CNGs) has been used to hyperpolarize neurons at very low light levels, which prevents them from firing action potentials.[8][9]

Other light-activated cyclases

Photoactivated guanylyl cyclases have been discovered in the aquatic fungi Blastocladiella emersonii[10][11] and Catenaria anguillulae.[12] Unlike PACs, these light-activated cyclases use retinal as their light sensor and are therefore rhodopsin guanylyl cyclases (RhGC). When expressed in Xenopus oocytes or mammalian neurons, RhGCs generate cGMP in response to green light.[12] Therefore, they are considered useful optogenetic tools to investigate cGMP signaling.[13]

References
  1. Ohki, Mio; Sugiyama, Kanako; Kawai, Fumihiro; Tanaka, Hitomi; Nihei, Yuuki; Unzai, Satoru; Takebe, Masumi; Matsunaga, Shigeru; Adachi, Shin-ichi; Shibayama, Naoya; Zhou, Zhiwen (2016-05-31). "Structural insight into photoactivation of an adenylate cyclase from a photosynthetic cyanobacterium". Proceedings of the National Academy of Sciences. 113 (24): 6659–6664. Bibcode:2016PNAS..113.6659O. doi:10.1073/pnas.1517520113. ISSN 0027-8424. PMC 4914150. PMID 27247413.
  2. Iseki, Mineo; Matsunaga, Shigeru; Murakami, Akio; Ohno, Kaoru; Shiga, Kiyoshi; Yoshida, Kazuichi; Sugai, Michizo; Takahashi, Tetsuo; Hori, Terumitsu; Watanabe, Masakatsu (2002-02-28). "A blue-light-activated adenylyl cyclase mediates photoavoidance in Euglena gracilis". Nature. 415 (6875): 1047–1051. Bibcode:2002Natur.415.1047I. doi:10.1038/4151047a. ISSN 1476-4687. PMID 11875575. S2CID 4420996.
  3. Stierl, Manuela; Stumpf, Patrick; Udwari, Daniel; Gueta, Ronnie; Hagedorn, Rolf; Losi, Aba; Gärtner, Wolfgang; Petereit, Linda; Efetova, Marina; Schwarzel, Martin; Oertner, Thomas G. (2011-01-14). "Light Modulation of Cellular cAMP by a Small Bacterial Photoactivated Adenylyl Cyclase, bPAC, of the Soil Bacterium Beggiatoa". Journal of Biological Chemistry. 286 (2): 1181–1188. doi:10.1074/jbc.M110.185496. ISSN 0021-9258. PMC 3020725. PMID 21030594.
  4. Yang, Shang; Constantin, Oana M.; Sachidanandan, Divya; Hofmann, Hannes; Kunz, Tobias C.; Kozjak-Pavlovic, Vera; Oertner, Thomas G.; Nagel, Georg; Kittel, Robert J.; Gee, Christine E.; Gao, Shiqiang (2021-10-18). "PACmn for improved optogenetic control of intracellular cAMP". BMC Biology. 19 (1): 227. doi:10.1186/s12915-021-01151-9. ISSN 1741-7007. PMC 8522238. PMID 34663304.
  5. Jansen, Vera; Alvarez, Luis; Balbach, Melanie; Strünker, Timo; Hegemann, Peter; Kaupp, U Benjamin; Wachten, Dagmar (2015-01-20). "Controlling fertilization and cAMP signaling in sperm by optogenetics". eLife. 4: e05161. doi:10.7554/eLife.05161. ISSN 2050-084X. PMC 4298566. PMID 25601414.
  6. Zhou, Zhiwen; Tanaka, Kenji F.; Matsunaga, Shigeru; Iseki, Mineo; Watanabe, Masakatsu; Matsuki, Norio; Ikegaya, Yuji; Koyama, Ryuta (2016-01-22). "Photoactivated adenylyl cyclase (PAC) reveals novel mechanisms underlying cAMP-dependent axonal morphogenesis". Scientific Reports. 6 (1): 19679. Bibcode:2016NatSR...519679Z. doi:10.1038/srep19679. ISSN 2045-2322. PMC 4726437. PMID 26795422.
  7. Zhang, Stephen X.; Lutas, Andrew; Yang, Shang; Diaz, Adriana; Fluhr, Hugo; Nagel, Georg; Gao, Shiqiang; Andermann, Mark L. (2021-09-09). "Hypothalamic dopamine neurons motivate mating through persistent cAMP signalling". Nature. 597 (7875): 245–249. Bibcode:2021Natur.597..245Z. doi:10.1038/s41586-021-03845-0. ISSN 0028-0836. PMC 8884112. PMID 34433964.
  8. Beck, Sebastian; Yu-Strzelczyk, Jing; Pauls, Dennis; Constantin, Oana M.; Gee, Christine E.; Ehmann, Nadine; Kittel, Robert J.; Nagel, Georg; Gao, Shiqiang (2018-10-02). "Synthetic Light-Activated Ion Channels for Optogenetic Activation and Inhibition". Frontiers in Neuroscience. 12: 643. doi:10.3389/fnins.2018.00643. ISSN 1662-453X. PMC 6176052. PMID 30333716.
  9. Bernal Sierra, Yinth Andrea; Rost, Benjamin R.; Pofahl, Martin; Fernandes, António Miguel; Kopton, Ramona A.; Moser, Sylvain; Holtkamp, Dominik; Masala, Nicola; Beed, Prateep; Tukker, John J.; Oldani, Silvia (2018). "Potassium channel-based optogenetic silencing". Nature Communications. 9 (1): 4611. Bibcode:2018NatCo...9.4611B. doi:10.1038/s41467-018-07038-8. ISSN 2041-1723. PMC 6218482. PMID 30397200.
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  11. Avelar, Gabriela M; Schumacher, Robert I; Zaini, Paulo A; Leonard, Guy; Richards, Thomas A; Gomes, Suely L (2014). "A Rhodopsin-Guanylyl Cyclase Gene Fusion Functions in Visual Perception in a Fungus". Current Biology. 24 (11): 1234–1240. doi:10.1016/j.cub.2014.04.009. PMC 4046227. PMID 24835457.
  12. Scheib, Ulrike; Broser, Matthias; Constantin, Oana M.; Yang, Shang; Gao, Shiqiang; Mukherjee, Shatanik; Stehfest, Katja; Nagel, Georg; Gee, Christine E.; Hegemann, Peter (2018). "Rhodopsin-cyclases for photocontrol of cGMP/cAMP and 2.3 Å structure of the adenylyl cyclase domain". Nature Communications. 9 (1): 2046. Bibcode:2018NatCo...9.2046S. doi:10.1038/s41467-018-04428-w. ISSN 2041-1723. PMC 5967339. PMID 29799525.
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