Nature Communications (Jan 2025)
Enhanced motivated behavior mediated by pharmacological targeting of the FGF14/Nav1.6 complex in nucleus accumbens neurons
- 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
Affiliations
- Nolan M. Dvorak
- Department of Pharmacology and Toxicology, University of Texas Medical Branch
- Paul A. Wadsworth
- Department of Pharmacology and Toxicology, University of Texas Medical Branch
- Guillermo Aquino-Miranda
- Department of Neurobiology and Anatomy, University of Texas Health Science Center
- Pingyuan Wang
- Department of Pharmacology and Toxicology, University of Texas Medical Branch
- Douglas S. Engelke
- Department of Neurobiology and Anatomy, University of Texas Health Science Center
- Jingheng Zhou
- Neurobiology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park
- Nghi Nguyen
- High-Throughput Research and Screening Center, Texas A&M Health Science Center
- Aditya K. Singh
- Department of Pharmacology and Toxicology, University of Texas Medical Branch
- Giuseppe Aceto
- Department of Neuroscience, Università Cattolica del Sacro Cuore
- Zahra Haghighijoo
- Department of Pharmacology and Toxicology, University of Texas Medical Branch
- Isabella I. Smith
- Department of Neurobiology and Anatomy, University of Texas Health Science Center
- Nana Goode
- Department of Pharmacology and Toxicology, University of Texas Medical Branch
- Mingxiang Zhou
- Department of Pharmacology and Toxicology, University of Texas Medical Branch
- Yosef Avchalumov
- Department of Pharmacology and Toxicology, University of Texas Medical Branch
- Evan P. Troendle
- Department of Chemistry, King’s College London 7 Trinity Street
- Cynthia M. Tapia
- Department of Pharmacology and Toxicology, University of Texas Medical Branch
- Haiying Chen
- Department of Pharmacology and Toxicology, University of Texas Medical Branch
- Reid T. Powell
- High-Throughput Research and Screening Center, Texas A&M Health Science Center
- Timothy J. Baumgartner
- Department of Pharmacology and Toxicology, University of Texas Medical Branch
- Jully Singh
- Department of Pharmacology and Toxicology, University of Texas Medical Branch
- Leandra Koff
- Department of Pharmacology and Toxicology, University of Texas Medical Branch
- Jessica Di Re
- Department of Pharmacology and Toxicology, University of Texas Medical Branch
- Ann E. Wadsworth
- Department of Pharmacology and Toxicology, University of Texas Medical Branch
- Mate Marosi
- Department of Pharmacology and Toxicology, University of Texas Medical Branch
- Marc R. Azar
- Behavioral Pharma Inc., 505 Coast Blvd. South, Suite 212
- Kristina Elias
- Behavioral Pharma Inc., 505 Coast Blvd. South, Suite 212
- Paul Lehmann
- Department of Pharmacology and Toxicology, University of Texas Medical Branch
- Yorkiris M. Mármol Contreras
- Department of Pharmacology and Toxicology, University of Texas Medical Branch
- Poonam Shah
- Department of Pharmacology and Toxicology, University of Texas Medical Branch
- Hector Gutierrez
- Department of Pharmacology and Toxicology, University of Texas Medical Branch
- Thomas A. Green
- Department of Pharmacology and Toxicology, University of Texas Medical Branch
- Martin B. Ulmschneider
- Department of Chemistry, King’s College London 7 Trinity Street
- Marcello D’Ascenzo
- Department of Neuroscience, Università Cattolica del Sacro Cuore
- Clifford Stephan
- High-Throughput Research and Screening Center, Texas A&M Health Science Center
- Guohong Cui
- Neurobiology Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park
- Fabricio H. Do Monte
- Department of Neurobiology and Anatomy, University of Texas Health Science Center
- Jia Zhou
- Department of Pharmacology and Toxicology, University of Texas Medical Branch
- Fernanda Laezza
- Department of Pharmacology and Toxicology, University of Texas Medical Branch
- DOI
- https://doi.org/10.1038/s41467-024-55554-7
- Journal volume & issue
-
Vol. 16,
no. 1
pp. 1 – 27
Abstract
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.
