title: Mechanisms of transient signaling via short and long prolactin receptor isoforms in female and male sensory neurons.
abstract: Prolactin (PRL) regulates activity of nociceptors and causes hyperalgesia in pain conditions. PRL enhances nociceptive responses by rapidly modulating channels in nociceptors. The molecular mechanisms underlying PRL-induced transient signaling in neurons are not well understood. Here we use a variety of cell biology and pharmacological approaches to show that PRL transiently enhanced capsaicin-evoked responses involve protein kinase C ε (PKCε) or phosphatidylinositol 3-kinase (PI3K) pathways in female rat trigeminal (TG) neurons. We next reconstituted PRL-induced signaling in a heterologous expression system and TG neurons from PRL receptor (PRLR)-null mutant mice by expressing rat PRLR-long isoform (PRLR-L), PRLR-short isoform (PRLR-S), or a mix of both. Results show that PRLR-S, but not PRLR-L, is capable of mediating PRL-induced transient enhancement of capsaicin responses in both male and female TG neurons. However, co-expression of PRLR-L with PRLR-S (1:1 ratio) leads to the inhibition of the transient PRL actions. Co-expression of PRLR-L deletion mutants with PRLR-S indicated that the cytoplasmic site adjacent to the trans-membrane domain of PRLR-L was responsible for inhibitory effects of PRLR-L. Furthermore, in situ hybridization and immunohistochemistry data indicate that in normal conditions, PRLR-L is expressed mainly in glia with little expression in rat sensory neurons (3-5%) and human nerves. The predominant PRLR form in TG neurons/nerves from rats and humans is PRLR-S. Altogether, PRL-induced transient signaling in sensory neurons is governed by PI3K or PKCε, mediated via the PRLR-S isoform, and transient effects mediated by PRLR-S are inhibited by presence of PRLR-L in these cells.
authors.affiliation: From the Departments of Endodontics and.
authors.forename: Sergei
authors.initials: S
authors.lastname: Belugin
authors.forename: Anibal R
authors.initials: AR
authors.lastname: Diogenes
authors.forename: Mayur J
authors.initials: MJ
authors.lastname: Patil
authors.forename: Erika
authors.initials: E
authors.lastname: Ginsburg
authors.forename: Michael A
authors.initials: MA
authors.lastname: Henry
authors.forename: Armen N
authors.initials: AN
authors.lastname: Akopian
mesh_terms: D000818:Animals; D016466:CHO Cells; D002478:Cells, Cultured; D003412:Cricetulus; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D020033:Protein Isoforms; D051744:Protein Kinase C-epsilon / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011981:Receptors, Prolactin / Q000235:genetics / Q000378:metabolism*; D011984:Sensory Receptor Cells / Q000166:cytology / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics*; D014070:Tooth / Q000378:metabolism / Q000502:physiology; D014276:Trigeminal Nerve / Q000166:cytology / Q000378:metabolism*
chemical_list: D020033:Protein Isoforms; D011981:Receptors, Prolactin; D019869:Phosphatidylinositol 3-Kinases; D051744:Protein Kinase C-epsilon
keywords: Neuroendocrinology; PI3-kinase (PI3K); Pain; Prolactin; Protein Kinase C (PKC)