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Molecular Pharmacology

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Research ArticleArticle

Serotonin-Mediated Activation of Serotonin Receptor Type 1 Oppositely Modulates Voltage-Gated Calcium Channel Currents in Rat Sensory Neurons Innervating Hindlimb Muscle

Laura Anselmi, Joyce S. Kim, Marc P. Kaufman, Shouhao Zhou and Victor Ruiz-Velasco
Molecular Pharmacology May 2022, 101 (5) 309-321; DOI: https://doi.org/10.1124/molpharm.121.000419
Laura Anselmi
Department of Anesthesiology and Perioperative Medicine (L.A., V.R.-V.) and Heart and Vascular Institute (J.S.K., M.P.K.), Penn State College of Medicine, Hershey, Pennsylvania; and Department of Public Health Sciences Division of Biostatistics and Bioinformatics, Penn State Cancer Institute, Next-Generation Therapies, Hershey, Pennsylvania (S.Z.)
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Joyce S. Kim
Department of Anesthesiology and Perioperative Medicine (L.A., V.R.-V.) and Heart and Vascular Institute (J.S.K., M.P.K.), Penn State College of Medicine, Hershey, Pennsylvania; and Department of Public Health Sciences Division of Biostatistics and Bioinformatics, Penn State Cancer Institute, Next-Generation Therapies, Hershey, Pennsylvania (S.Z.)
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Marc P. Kaufman
Department of Anesthesiology and Perioperative Medicine (L.A., V.R.-V.) and Heart and Vascular Institute (J.S.K., M.P.K.), Penn State College of Medicine, Hershey, Pennsylvania; and Department of Public Health Sciences Division of Biostatistics and Bioinformatics, Penn State Cancer Institute, Next-Generation Therapies, Hershey, Pennsylvania (S.Z.)
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Shouhao Zhou
Department of Anesthesiology and Perioperative Medicine (L.A., V.R.-V.) and Heart and Vascular Institute (J.S.K., M.P.K.), Penn State College of Medicine, Hershey, Pennsylvania; and Department of Public Health Sciences Division of Biostatistics and Bioinformatics, Penn State Cancer Institute, Next-Generation Therapies, Hershey, Pennsylvania (S.Z.)
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Victor Ruiz-Velasco
Department of Anesthesiology and Perioperative Medicine (L.A., V.R.-V.) and Heart and Vascular Institute (J.S.K., M.P.K.), Penn State College of Medicine, Hershey, Pennsylvania; and Department of Public Health Sciences Division of Biostatistics and Bioinformatics, Penn State Cancer Institute, Next-Generation Therapies, Hershey, Pennsylvania (S.Z.)
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Abstract

Serotonin (5-HT) is a multifaceted neurotransmitter that has been described to play a role as a peripheral inflammatory mediator when released in ischemic or injured muscle. Dorsal root ganglia (DRG) neurons are key sensors of noxious stimuli that are released under inflammatory conditions or mechanical stress. Little information is available on the specific 5-HT receptor subtypes expressed in primary afferents that help regulate reflex pressor responses. In the present study, the whole-cell patch-clamp technique was employed to examine the modulation of voltage-gated calcium channel (CaV) 2.2 currents by 5-HT and to identify the 5-HT receptor subtype(s) mediating this response in acutely dissociated rat DRG neurons innervating triceps surae muscle. Our results indicate that exposure of 1,1’-dioctadecyl-3,3,3′,3′-tetramethylindocarbocyanine perchlorate (DiI)-labeled DRG neurons to 5-HT can exert three modulatory effects on CaV currents: high inhibition, low inhibition, and enhancement. Both 5-HT-mediated inhibition responses were blocked after pretreatment with pertussis toxin (PTX), indicating that 5-HT receptors are coupled to CaV2.2 via Gαi/o protein subunits. Application of selective serotonin receptor type 1 (5-HT1) agonists revealed that modulation of CaV2.2 currents occurs primarily after 5-HT1A receptor subtype stimulation and minimally from 5-HT1D activation. Finally, the intrathecal administration of the selective 5-HT1A receptor agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), significantly (P < 0.05) decreased the pressor response induced by intra-arterial administration of lactic acid. This suggests that 5-HT1A receptors are expressed presynaptically on primary afferent neurons innervating triceps surae muscle. Our findings indicate that preferential stimulation of 5-HT1 receptors, expressed on thin fiber muscle afferents, serves to regulate the reflex pressor response to metabolic stimuli.

SIGNIFICANCE STATEMENT The monoamine serotonin (5-HT), released under ischemic conditions, can contribute to the development of inflammation that negatively affects the exercise pressor reflex. The 5-HT receptor subtype and signaling pathway that underlies calcium channel modulation in dorsal root ganglia afferents, innervating hindlimb muscles, are unknown. We show that 5-HT can either block (primarily via serotonin receptor type 1 (5-HT1)A subtypes) or enhance voltage-gated calcium channel (CaV2.2) currents. Our findings suggest 5-HT exhibits receptor subtype selectivity, providing a complexity of cellular responses.

Footnotes

    • Received September 27, 2021.
    • Accepted February 5, 2022.
  • This article was supported by National Institutes of Health National Heart, Lung, and Blood Institute [Grant P01-HL134609].

  • No author has an actual or perceived conflict of interest with the contents of this article.

  • https://doi.org/10.1124/molpharm.121.000419.

  • Copyright © 2022 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 101 (5)
Molecular Pharmacology
Vol. 101, Issue 5
1 May 2022
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Research ArticleArticle

Diverse 5-HT Pathways Modulate Ca2+ Currents in DRG Neurons

Laura Anselmi, Joyce S. Kim, Marc P. Kaufman, Shouhao Zhou and Victor Ruiz-Velasco
Molecular Pharmacology May 1, 2022, 101 (5) 309-321; DOI: https://doi.org/10.1124/molpharm.121.000419

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Research ArticleArticle

Diverse 5-HT Pathways Modulate Ca2+ Currents in DRG Neurons

Laura Anselmi, Joyce S. Kim, Marc P. Kaufman, Shouhao Zhou and Victor Ruiz-Velasco
Molecular Pharmacology May 1, 2022, 101 (5) 309-321; DOI: https://doi.org/10.1124/molpharm.121.000419
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