Universität zu Köln

Isensee, Joerg ORCID: 0000-0002-3390-0051, Krahe, Leonhardt, Moeller, Katharina, Pereira, Vanessa ORCID: 0000-0001-5416-6856, Sexton, Jane E., Sun, Xiaohui, Emery, Edward ORCID: 0000-0001-9723-8661, Wood, John N. and Hucho, Tim ORCID: 0000-0002-4147-9308 (2017). Synergistic regulation of serotonin and opioid signaling contribute to pain insensitivity in Na(v)1.7 knockout mice. Sci. Signal., 10 (461). WASHINGTON: AMER ASSOC ADVANCEMENT SCIENCE. ISSN 1937-9145

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Abstract

Genetic loss of the voltage-gated sodium channel Nav1.7 (Na(v)1.7(-/-)) results in lifelong insensitivity to pain inmice and humans. One underlying cause is an increase in the production of endogenous opioids in sensory neurons. We analyzed whether Na(v)1.7 deficiency altered nociceptive heterotrimeric guanine nucleotide-binding protein-coupled receptor (GPCR) signaling, such as initiated by GPCRs that respond to serotonin (pronociceptive) or opioids (antinociceptive), in sensory neurons. We found that the nociceptive neurons of Na(v)1.7 knockout (Na(v)1.7(-/-)) mice, but not those of Na(v)1.8 knockout (Na(v)1.8(-/-)) mice, exhibited decreased pronociceptive serotonergic signaling through the 5-HT4 receptors, which are G alpha(s)-coupled GPCRs that stimulate the production of cyclic adenosinemonophosphate resulting in protein kinase A (PKA) activity, as well as reduced abundance of the RIIb regulatory subunit of PKA. Simultaneously, the efficacy of antinociceptive opioid signaling mediated by the G alpha(i)-coupled mu opioid receptors was increased. Consequently, opioids inhibited more efficiently tetrodotoxin-resistant sodium currents, which are important for pain-initiating neuronal activity in nociceptive neurons. Thus, Na(v)1.7 controls the efficacy and balance of GPCR-mediated pro-and antinociceptive intracellular signaling, such that without Na(v)1.7, the balance is shifted toward antinociception, resulting in lifelong endogenous analgesia.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Isensee, Joerg UNSPECIFIED orcid.org/0000-0002-3390-0051 UNSPECIFIED Krahe, Leonhardt UNSPECIFIED UNSPECIFIED UNSPECIFIED Moeller, Katharina UNSPECIFIED UNSPECIFIED UNSPECIFIED Pereira, Vanessa UNSPECIFIED orcid.org/0000-0001-5416-6856 UNSPECIFIED Sexton, Jane E. UNSPECIFIED UNSPECIFIED UNSPECIFIED Sun, Xiaohui UNSPECIFIED UNSPECIFIED UNSPECIFIED Emery, Edward UNSPECIFIED orcid.org/0000-0001-9723-8661 UNSPECIFIED Wood, John N. UNSPECIFIED UNSPECIFIED UNSPECIFIED Hucho, Tim UNSPECIFIED orcid.org/0000-0002-4147-9308 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-242650
DOI:	10.1126/scisignal.aah4874
Journal or Publication Title:	Sci. Signal.
Volume:	10
Number:	461
Date:	2017
Publisher:	AMER ASSOC ADVANCEMENT SCIENCE
Place of Publication:	WASHINGTON
ISSN:	1937-9145
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language ADENYLATE-CYCLASE; SODIUM-CHANNELS; PROTEIN-KINASE; 5-HT4 RECEPTOR; PHOSPHORYLATION; 5-HYDROXYTRYPTAMINE; DESENSITIZATION; EXCITABILITY; AGONIST; BINDING Multiple languages Biochemistry & Molecular Biology; Cell Biology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/24265