Chemogenetics

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Chemogenetics is the process by which macromolecules can be engineered to interact with previously unrecognized small molecules. Chemogenetics as a term was originally coined to describe the observed effects of mutations on chalcone isomerase activity on substrate specificities in the flowers of Dianthus caryophyllus . [1] This method is very similar to optogenetics; however, it uses chemically engineered molecules and ligands instead of light and light-sensitive channels known as opsins.

Contents

In recent research projects, chemogenetics has been widely used to understand the relationship between brain activity and behavior. Prior to chemogenetics, researchers used methods such as transcranial magnetic stimulation and deep brain stimulation to study the relationship between neuronal activity and behavior. [2]

Comparison to optogenetics

Optogenetics and chemogenetics are the more recent and popular methods used to study this relationship. Both of these methods target specific brain circuits and cell population to influence cell activity. However, they use different procedures to accomplish this task. Optogenetics uses light-sensitive channels and pumps that are virally introduced into neurons. Cells' activity, having these channels, can then be manipulated by light. Chemogenetics, on the other hand, uses chemically engineered receptors and exogenous molecules specific for those receptors, to affect the activity of those cells. The engineered macromolecules used to design these receptors include nucleic acid hybrids, [3] kinases, [4] variety of metabolic enzymes, [5] [6] and G-protein coupled receptors such as DREADDs. [7] [8] [9] [10]

DREADDs are the most common G protein–coupled receptors used in chemogenetics. [11] These receptors solely get activated by the drug of interest (inert molecule) and influence physiological and neural processes that take place within and outside of the central nervous system.[ citation needed ]

Chemogenetics has recently been favored over optogenetics, and it avoids some of the challenges of optogenetics. Chemogenetics does not require the expensive light equipment, and therefore, is more accessible. The resolution in optogenetics declines due to light scattering and illuminance declined levels as the distance between the subject and the light source increases. These factors, therefore, don’t allow for all cells to be affected by light and lead to a lower spatial resolution. Chemogenetics, however, does not require light usage and therefore can achieve a higher spatial resolution. [12]

Applications

G-protein coupled receptors' usage and chemogenetics are nowadays the targets for many of the pharmaceutical companies to cure and alleviate symptoms of diseases that involve all tissues of the body. [13] More specifically, DREADDs have been used to explore treatment options for various neurodegenerative and psychological conditions such as Parkinson’s disease, depression, anxiety, and addiction. These aforementioned conditions involve processes that occur within and outside of the nervous system involving neurotransmitters such as gamma-aminobutyric acid and glutamate. [14] Chemogenetics has therefore been used in pharmacology to adjust the levels of such neurotransmitters in specific neuron while minimizing the side effects of treatment. To treat and relieve the symptoms of any disease using the DREADDs, these receptors are delivered to the area of interest via viral transduction.[ citation needed ]

Recently some studies have considered using a new method called retro DREADDs. This method allows specific neuronal pathways to be studied under cellular resolution. Unlike classic DREADDs, this method is usually used in wild type animals, and these receptors are given to the targeted cells via injection of two viral vectors. [2]

Animal Models

DREADDS have been used in many animal models (e.g., mice and other non-primate animals) to target and influence the activity of various cells. Chemogenetics used in animals assists with demonstrating human disease models such as Parkinson's disease. Having this information allows scientists understand whether viral expression of DREADD proteins, both in-vivo enhancers and inhibitors of neuronal function can be used to bidirectionally affect the behaviors and the activity of the involved neurons. Recent studies have shown that DREADDs were successfully used to treat the motor deficits of rats modeling Parkinson's disease. [15] Other studies have had successes linking the usage of DREADDs and influencing drug seeking and drug sensitization behavior. [14]

The progression of chemogenetics from rodents to non-human primates has been slow due to increased demand in time and expense surrounding these projects. However, some recent studies in 2016 have been able to demonstrate successes showing that silencing the activity of neurons in the orbitofrontal cortex along with the removal of rhinal cortex, restricted the reward task performance in macaques. [16]

Limitation and future directions

Chemogenetics and usage of DREADDs have allowed researchers to advance in biomedical research areas including many neurodegenerative and psychiatric conditions. Chemogenetics have been used in these fields to induce specific and reversible brain lesions and therefore, study specific activities of neuron population. Although chemogenetics offers specificity and high spatial resolution, it still faces some challenges when used in investigating neuropsychiatric disorders. Neuropsychiatric disorders usually have a complex nature where lesions in the brain have not been identified as the main cause. Chemogenetics has been used to reverse some of the deficits revolving such conditions; however, it has not been able to identify the main cause of neuropsychiatric diseases and cure these conditions completely due to complex nature of these conditions. Nevertheless, chemogenetics has been used successfully in a preclinical model of drug-resistant epilepsy, where seizures arise from a discrete part of the brain. [17]

See also

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References

  1. ↑ Forkmann G, Dangelmayr B (June 1980). "Genetic control of chalcone isomerase activity in flowers of Dianthus caryophyllus". Biochemical Genetics. 18 (5–6): 519–27. doi:10.1007/bf00484399. PMID   7437010. S2CID   19572782.
  2. 1 2 Dobrzanski G, Kossut M (April 2017). "Application of the DREADD technique in biomedical brain research". Pharmacological Reports. 69 (2): 213–221. doi:10.1016/j.pharep.2016.10.015. PMID   28092807. S2CID   25055148.
  3. ↑ Strobel SA, Ortoleva-Donnelly L, Ryder SP, Cate JH, Moncoeur E (January 1998). "Complementary sets of noncanonical base pairs mediate RNA helix packing in the group I intron active site". Nature Structural Biology. 5 (1): 60–6. doi:10.1038/nsb0198-60. PMID   9437431. S2CID   20067957.
  4. ↑ Bishop AC, Shah K, Liu Y, Witucki L, Kung C, Shokat KM (February 1998). "Design of allele-specific inhibitors to probe protein kinase signaling". Current Biology. 8 (5): 257–66. doi: 10.1016/s0960-9822(98)70198-8 . PMID   9501066.
  5. ↑ Collot J, Gradinaru J, Humbert N, Skander M, Zocchi A, Ward TR (July 2003). "Artificial metalloenzymes for enantioselective catalysis based on biotin-avidin". Journal of the American Chemical Society. 125 (30): 9030–1. doi:10.1021/ja035545i. PMID   15369356.
  6. ↑ Häring D, Distefano MD (2001). "Enzymes by design: chemogenetic assembly of transamination active sites containing lysine residues for covalent catalysis". Bioconjugate Chemistry. 12 (3): 385–90. doi:10.1021/bc000117c. PMID   11353536.
  7. ↑ Strader CD, Gaffney T, Sugg EE, Candelore MR, Keys R, Patchett AA, Dixon RA (January 1991). "Allele-specific activation of genetically engineered receptors". The Journal of Biological Chemistry. 266 (1): 5–8. doi: 10.1016/S0021-9258(18)52392-9 . PMID   1670767.
  8. ↑ Coward P, Wada HG, Falk MS, Chan SD, Meng F, Akil H, Conklin BR (January 1998). "Controlling signaling with a specifically designed Gi-coupled receptor". Proceedings of the National Academy of Sciences of the United States of America. 95 (1): 352–7. Bibcode:1998PNAS...95..352C. doi: 10.1073/pnas.95.1.352 . PMC   18222 . PMID   9419379.
  9. ↑ Westkaemper RB, Hyde EG, Choudhary MS, Khan N, Gelbar EI, Glennon RA, Roth BL (1999). "Engineering a region of bulk tolerance in the 5-HT2A receptor". European Journal of Medicinal Chemistry. 34 (5): 441–447. doi:10.1016/s0223-5234(99)80094-4.
  10. ↑ Armbruster BN, Li X, Pausch MH, Herlitze S, Roth BL (March 2007). "Evolving the lock to fit the key to create a family of G protein-coupled receptors potently activated by an inert ligand". Proceedings of the National Academy of Sciences of the United States of America. 104 (12): 5163–8. doi: 10.1073/pnas.0700293104 . PMC   1829280 . PMID   17360345.
  11. ↑ Roth BL (February 2016). "DREADDs for Neuroscientists". Neuron. 89 (4): 683–94. doi:10.1016/j.neuron.2016.01.040. PMC   4759656 . PMID   26889809.
  12. ↑ Montgomery KL, Yeh AJ, Ho JS, Tsao V, Mohan Iyer S, Grosenick L, Ferenczi EA, Tanabe Y, Deisseroth K, Delp SL, Poon AS (October 2015). "Wirelessly powered, fully internal optogenetics for brain, spinal and peripheral circuits in mice". Nature Methods. 12 (10): 969–74. doi:10.1038/nmeth.3536. PMC   5507210 . PMID   26280330.
  13. ↑ Smith RS, Hu R, DeSouza A, Eberly CL, Krahe K, Chan W, Araneda RC (July 2015). "Differential Muscarinic Modulation in the Olfactory Bulb". The Journal of Neuroscience. 35 (30): 10773–85. doi:10.1523/JNEUROSCI.0099-15.2015. PMC   4518052 . PMID   26224860.
  14. 1 2 Volkow ND, Koob GF, McLellan AT (January 2016). "Neurobiologic Advances from the Brain Disease Model of Addiction". The New England Journal of Medicine. 374 (4): 363–71. doi:10.1056/nejmra1511480. PMC   6135257 . PMID   26816013.
  15. ↑ Pienaar IS, Gartside SE, Sharma P, De Paola V, Gretenkord S, Withers D, Elson JL, Dexter DT (September 2015). "Pharmacogenetic stimulation of cholinergic pedunculopontine neurons reverses motor deficits in a rat model of Parkinson's disease". Molecular Neurodegeneration. 10: 47. doi: 10.1186/s13024-015-0044-5 . PMC   4580350 . PMID   26394842.
  16. ↑ Galvan A, Caiola MJ, Albaugh DL (March 2018). "Advances in optogenetic and chemogenetic methods to study brain circuits in non-human primates". Journal of Neural Transmission. 125 (3): 547–563. doi:10.1007/s00702-017-1697-8. PMC   5572535 . PMID   28238201.
  17. ↑ Kätzel D, Nicholson E, Schorge S, Walker MC, Kullmann DM (May 2014). "Chemical-genetic attenuation of focal neocortical seizures". Nature Communications. 5: 3847. Bibcode:2014NatCo...5.3847K. doi:10.1038/ncomms4847. PMC   4050272 . PMID   24866701.
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