Photoactivated adenylyl cyclase explained

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.[1] Small but potent PACs were identified in the genome of the bacteria Beggiatoa (bPAC) and Oscillatoria acuminata (OaPAC).[2] While natural bPAC has some enzymatic activity in the absence of light, variants with no dark activity have been engineered (PACmn).[3]

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.[4] When expressed in neurons, illumination changes the branching pattern of growing axons.[5] PAC has been used in mice to clarify the function of neurons in the hypothalamus, which use cAMP signaling to control mating behavior.[6] 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.[7] [8]

Rhodopsin guanylyl cyclases

Photoactivated guanylyl cyclases have been discovered in the aquatic fungi Blastocladiella emersonii[9] [10] and Catenaria anguillulae.[11] 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. Therefore, they are considered useful optogenetic tools to investigate cGMP signaling.[12]

Notes and References

  1. 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. en. 415. 6875. 1047–1051. 10.1038/4151047a. 11875575. 1476-4687. 2002Natur.415.1047I. 4420996.
  2. 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. en. 286. 2. 1181–1188. 10.1074/jbc.M110.185496. 21030594. 3020725. 0021-9258. free .
  3. 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. 34663304. 10.1186/s12915-021-01151-9. 8522238 . 1741-7007 . free .
  4. 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. en. 4. e05161. 10.7554/eLife.05161. 25601414. 4298566. 2050-084X . free .
  5. 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. 10.1038/srep19679. 26795422. 4726437. 2045-2322. 2016NatSR...519679Z.
  6. 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. en. 597. 7875. 245–249. 10.1038/s41586-021-03845-0. 34433964 . 8884112 . 2021Natur.597..245Z . 0028-0836.
  7. 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. 10.3389/fnins.2018.00643. 30333716. 6176052. 1662-453X. free .
  8. 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. en. 9. 1. 4611. 10.1038/s41467-018-07038-8. 30397200. 6218482. 2041-1723. 2018NatCo...9.4611B.
  9. Scheib. Ulrike. Stehfest. Katja. Gee. Christine E.. Körschen. Heinz G.. Fudim. Roman. Oertner. Thomas G.. Hegemann. Peter. 2015-08-11. The rhodopsin–guanylyl cyclase of the aquatic fungus Blastocladiella emersonii enables fast optical control of cGMP signaling. Science Signaling. en. 8. 389. rs8. 10.1126/scisignal.aab0611. 26268609. 13140205. 1945-0877.
  10. 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. en. 24. 11. 1234–1240. 10.1016/j.cub.2014.04.009. 4046227. 24835457.
  11. 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. en. 9. 1. 2046. 10.1038/s41467-018-04428-w. 29799525. 5967339. 2041-1723. 2018NatCo...9.2046S.
  12. Rost. Benjamin R.. Schneider-Warme. Franziska. Schmitz. Dietmar. Hegemann. Peter. 2017. Optogenetic Tools for Subcellular Applications in Neuroscience. Neuron. en. 96. 3. 572–603. 10.1016/j.neuron.2017.09.047. 29096074. free.

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