Enhanced motivated behavior mediated by pharmacological targeting of the FGF14/Nav1.6 complex in nucleus accumbens neurons
Abstract Protein/protein interactions (PPI) play crucial roles in neuronal functions. Yet, their potential as drug targets for brain disorders remains underexplored. The fibroblast growth factor 14 (FGF14)/voltage-gated Na+ channel 1.6 (Nav1.6) complex regulates excitability of medium spiny neurons...
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2025-01-01
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| Online Access: | https://doi.org/10.1038/s41467-024-55554-7 |
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| author | Nolan M. Dvorak Paul A. Wadsworth Guillermo Aquino-Miranda Pingyuan Wang Douglas S. Engelke Jingheng Zhou Nghi Nguyen Aditya K. Singh Giuseppe Aceto Zahra Haghighijoo Isabella I. Smith Nana Goode Mingxiang Zhou Yosef Avchalumov Evan P. Troendle Cynthia M. Tapia Haiying Chen Reid T. Powell Timothy J. Baumgartner Jully Singh Leandra Koff Jessica Di Re Ann E. Wadsworth Mate Marosi Marc R. Azar Kristina Elias Paul Lehmann Yorkiris M. Mármol Contreras Poonam Shah Hector Gutierrez Thomas A. Green Martin B. Ulmschneider Marcello D’Ascenzo Clifford Stephan Guohong Cui Fabricio H. Do Monte Jia Zhou Fernanda Laezza |
| author_facet | Nolan M. Dvorak Paul A. Wadsworth Guillermo Aquino-Miranda Pingyuan Wang Douglas S. Engelke Jingheng Zhou Nghi Nguyen Aditya K. Singh Giuseppe Aceto Zahra Haghighijoo Isabella I. Smith Nana Goode Mingxiang Zhou Yosef Avchalumov Evan P. Troendle Cynthia M. Tapia Haiying Chen Reid T. Powell Timothy J. Baumgartner Jully Singh Leandra Koff Jessica Di Re Ann E. Wadsworth Mate Marosi Marc R. Azar Kristina Elias Paul Lehmann Yorkiris M. Mármol Contreras Poonam Shah Hector Gutierrez Thomas A. Green Martin B. Ulmschneider Marcello D’Ascenzo Clifford Stephan Guohong Cui Fabricio H. Do Monte Jia Zhou Fernanda Laezza |
| author_sort | Nolan M. Dvorak |
| collection | DOAJ |
| description | Abstract Protein/protein interactions (PPI) play crucial roles in neuronal functions. Yet, their potential as drug targets for brain disorders remains underexplored. The fibroblast growth factor 14 (FGF14)/voltage-gated Na+ channel 1.6 (Nav1.6) complex regulates excitability of medium spiny neurons (MSN) of the nucleus accumbens (NAc), a central hub of reward circuitry that controls motivated behaviors. Here, we identified compound 1028 (IUPAC: ethyl 3-(2-(3-(hydroxymethyl)-1H-indol-1-yl)acetamido)benzoate), a brain-permeable small molecule that targets FGF14R117, a critical residue located within a druggable pocket at the FGF14/Nav1.6 PPI interface. We found that 1028 modulates FGF14/Nav1.6 complex assembly and depolarizes the voltage-dependence of Nav1.6 channel inactivation with nanomolar potency by modulating the intramolecular interaction between the III-IV linker and C-terminal domain of the Nav1.6 channel. Consistent with the compound’s effects on Nav1.6 channel inactivation, 1028 enhances MSN excitability ex vivo and accumbal neuron firing rate in vivo in murine models. Systemic administration of 1028 maintains behavioral motivation preferentially during motivationally deficient conditions in murine models. These behavioral effects were abrogated by in vivo gene silencing of Fgf14 in the NAc and were accompanied by a selective reduction in accumbal dopamine levels during reward consumption in murine models. These findings underscore the potential to selectively regulate complex behaviors associated with neuropsychiatric disorders through targeting of PPIs in neurons. |
| format | Article |
| id | doaj-art-5bdbd67a4c3444fa90812b37bab635dc |
| institution | DOAJ |
| issn | 2041-1723 |
| language | English |
| publishDate | 2025-01-01 |
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| series | Nature Communications |
| spelling | doaj-art-5bdbd67a4c3444fa90812b37bab635dc2025-08-20T02:46:13ZengNature PortfolioNature Communications2041-17232025-01-0116112710.1038/s41467-024-55554-7Enhanced motivated behavior mediated by pharmacological targeting of the FGF14/Nav1.6 complex in nucleus accumbens neuronsNolan M. Dvorak0Paul A. Wadsworth1Guillermo Aquino-Miranda2Pingyuan Wang3Douglas S. Engelke4Jingheng Zhou5Nghi Nguyen6Aditya K. Singh7Giuseppe Aceto8Zahra Haghighijoo9Isabella I. Smith10Nana Goode11Mingxiang Zhou12Yosef Avchalumov13Evan P. Troendle14Cynthia M. Tapia15Haiying Chen16Reid T. Powell17Timothy J. Baumgartner18Jully Singh19Leandra Koff20Jessica Di Re21Ann E. Wadsworth22Mate Marosi23Marc R. Azar24Kristina Elias25Paul Lehmann26Yorkiris M. Mármol Contreras27Poonam Shah28Hector Gutierrez29Thomas A. Green30Martin B. Ulmschneider31Marcello D’Ascenzo32Clifford Stephan33Guohong Cui34Fabricio H. Do Monte35Jia Zhou36Fernanda Laezza37Department of Pharmacology and Toxicology, University of Texas Medical BranchDepartment of Pharmacology and Toxicology, University of Texas Medical BranchDepartment of Neurobiology and Anatomy, University of Texas Health Science CenterDepartment of Pharmacology and Toxicology, University of Texas Medical BranchDepartment of Neurobiology and Anatomy, University of Texas Health Science CenterNeurobiology Laboratory, National Institute of Environmental Health Sciences, Research Triangle ParkHigh-Throughput Research and Screening Center, Texas A&M Health Science CenterDepartment of Pharmacology and Toxicology, University of Texas Medical BranchDepartment of Neuroscience, Università Cattolica del Sacro CuoreDepartment of Pharmacology and Toxicology, University of Texas Medical BranchDepartment of Neurobiology and Anatomy, University of Texas Health Science CenterDepartment of Pharmacology and Toxicology, University of Texas Medical BranchDepartment of Pharmacology and Toxicology, University of Texas Medical BranchDepartment of Pharmacology and Toxicology, University of Texas Medical BranchDepartment of Chemistry, King’s College London 7 Trinity StreetDepartment of Pharmacology and Toxicology, University of Texas Medical BranchDepartment of Pharmacology and Toxicology, University of Texas Medical BranchHigh-Throughput Research and Screening Center, Texas A&M Health Science CenterDepartment of Pharmacology and Toxicology, University of Texas Medical BranchDepartment of Pharmacology and Toxicology, University of Texas Medical BranchDepartment of Pharmacology and Toxicology, University of Texas Medical BranchDepartment of Pharmacology and Toxicology, University of Texas Medical BranchDepartment of Pharmacology and Toxicology, University of Texas Medical BranchDepartment of Pharmacology and Toxicology, University of Texas Medical BranchBehavioral Pharma Inc., 505 Coast Blvd. South, Suite 212Behavioral Pharma Inc., 505 Coast Blvd. South, Suite 212Department of Pharmacology and Toxicology, University of Texas Medical BranchDepartment of Pharmacology and Toxicology, University of Texas Medical BranchDepartment of Pharmacology and Toxicology, University of Texas Medical BranchDepartment of Pharmacology and Toxicology, University of Texas Medical BranchDepartment of Pharmacology and Toxicology, University of Texas Medical BranchDepartment of Chemistry, King’s College London 7 Trinity StreetDepartment of Neuroscience, Università Cattolica del Sacro CuoreHigh-Throughput Research and Screening Center, Texas A&M Health Science CenterNeurobiology Laboratory, National Institute of Environmental Health Sciences, Research Triangle ParkDepartment of Neurobiology and Anatomy, University of Texas Health Science CenterDepartment of Pharmacology and Toxicology, University of Texas Medical BranchDepartment of Pharmacology and Toxicology, University of Texas Medical BranchAbstract Protein/protein interactions (PPI) play crucial roles in neuronal functions. Yet, their potential as drug targets for brain disorders remains underexplored. The fibroblast growth factor 14 (FGF14)/voltage-gated Na+ channel 1.6 (Nav1.6) complex regulates excitability of medium spiny neurons (MSN) of the nucleus accumbens (NAc), a central hub of reward circuitry that controls motivated behaviors. Here, we identified compound 1028 (IUPAC: ethyl 3-(2-(3-(hydroxymethyl)-1H-indol-1-yl)acetamido)benzoate), a brain-permeable small molecule that targets FGF14R117, a critical residue located within a druggable pocket at the FGF14/Nav1.6 PPI interface. We found that 1028 modulates FGF14/Nav1.6 complex assembly and depolarizes the voltage-dependence of Nav1.6 channel inactivation with nanomolar potency by modulating the intramolecular interaction between the III-IV linker and C-terminal domain of the Nav1.6 channel. Consistent with the compound’s effects on Nav1.6 channel inactivation, 1028 enhances MSN excitability ex vivo and accumbal neuron firing rate in vivo in murine models. Systemic administration of 1028 maintains behavioral motivation preferentially during motivationally deficient conditions in murine models. These behavioral effects were abrogated by in vivo gene silencing of Fgf14 in the NAc and were accompanied by a selective reduction in accumbal dopamine levels during reward consumption in murine models. These findings underscore the potential to selectively regulate complex behaviors associated with neuropsychiatric disorders through targeting of PPIs in neurons.https://doi.org/10.1038/s41467-024-55554-7 |
| spellingShingle | Nolan M. Dvorak Paul A. Wadsworth Guillermo Aquino-Miranda Pingyuan Wang Douglas S. Engelke Jingheng Zhou Nghi Nguyen Aditya K. Singh Giuseppe Aceto Zahra Haghighijoo Isabella I. Smith Nana Goode Mingxiang Zhou Yosef Avchalumov Evan P. Troendle Cynthia M. Tapia Haiying Chen Reid T. Powell Timothy J. Baumgartner Jully Singh Leandra Koff Jessica Di Re Ann E. Wadsworth Mate Marosi Marc R. Azar Kristina Elias Paul Lehmann Yorkiris M. Mármol Contreras Poonam Shah Hector Gutierrez Thomas A. Green Martin B. Ulmschneider Marcello D’Ascenzo Clifford Stephan Guohong Cui Fabricio H. Do Monte Jia Zhou Fernanda Laezza Enhanced motivated behavior mediated by pharmacological targeting of the FGF14/Nav1.6 complex in nucleus accumbens neurons Nature Communications |
| title | Enhanced motivated behavior mediated by pharmacological targeting of the FGF14/Nav1.6 complex in nucleus accumbens neurons |
| title_full | Enhanced motivated behavior mediated by pharmacological targeting of the FGF14/Nav1.6 complex in nucleus accumbens neurons |
| title_fullStr | Enhanced motivated behavior mediated by pharmacological targeting of the FGF14/Nav1.6 complex in nucleus accumbens neurons |
| title_full_unstemmed | Enhanced motivated behavior mediated by pharmacological targeting of the FGF14/Nav1.6 complex in nucleus accumbens neurons |
| title_short | Enhanced motivated behavior mediated by pharmacological targeting of the FGF14/Nav1.6 complex in nucleus accumbens neurons |
| title_sort | enhanced motivated behavior mediated by pharmacological targeting of the fgf14 nav1 6 complex in nucleus accumbens neurons |
| url | https://doi.org/10.1038/s41467-024-55554-7 |
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