title: Colitis-induced bladder afferent neuronal activation is regulated by BDNF through PLCγ pathway.
abstract: Patients with inflammatory bowel disease (IBD) or irritable bowel syndrome (IBS) often experience increased sensory responsiveness in the urinary bladder reflecting neurogenic bladder overactivity. Here we demonstrate that colitis-induced up-regulation of the phospholipase C gamma (PLCγ) pathway downstream of brain-derived neurotrophic factor (BDNF) in bladder afferent neurons in the dorsal root ganglia (DRG) plays essential roles in activating these neurons thereby leading to bladder hyperactivity. Upon induction of colitis with 2,4,6-trinitrobenzenesulfonic acid (TNBS) in rats, we found that the phosphorylation (activation) level of cAMP responsive element-binding (p-CREB) protein, a molecular switch of neuronal plasticity, was increased in specifically labeled bladder afferent neurons in the thoracolumbar and lumbosacral DRGs. In rats having reduced levels of BDNF (BDNF+/-), colitis failed to elevate CREB protein activity in bladder afferent neurons. Physiological examination also demonstrated that colitis-induced urinary frequency was not shown in BDNF+/-rats, implicating an essential role of BDNF in mediating colon-to-bladder sensory cross-sensitization. We further implemented in vivo and in vitro studies and demonstrated that BDNF-mediated colon-to-bladder sensory cross-activation involved the TrkB-PLCγ-calcium/calmodulin-dependent protein kinase II (CaMKII) cascade. In contrast, the PI3K/Akt pathway was not activated in bladder afferent neurons during colitis and was not involved in BDNF action in the DRG. Our results suggest that colon-to-bladder sensory cross-sensitization is regulated by specific signal transduction initiated by the up-regulation of BDNF in the DRG.
authors.affiliation: Department of Physiology and Biophysics, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Chunmei
authors.initials: C
authors.lastname: Xia
authors.affiliation: Department of Physiology and Biophysics, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Shanwei
authors.initials: S
authors.lastname: Shen
authors.affiliation: Department of Physiology and Biophysics, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA.
authors.forename: Fiza
authors.initials: F
authors.lastname: Hashmi
authors.affiliation: Department of Physiology and Biophysics, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA. Electronic address: liya.qiao@vcuhealth.org.
authors.forename: Li-Ya
authors.initials: LY
authors.lastname: Qiao
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D050882:CREB-Binding Protein / Q000378:metabolism; D003092:Colitis / Q000139:chemically induced / Q000473:pathology*; D004195:Disease Models, Animal; D005727:Ganglia, Spinal / Q000473:pathology*; D008297:Male; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D051966:Phospholipase C gamma / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014302:Trinitrobenzenesulfonic Acid / Q000633:toxicity; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D001743:Urinary Bladder / Q000294:innervation
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D014302:Trinitrobenzenesulfonic Acid; D050882:CREB-Binding Protein; D051966:Phospholipase C gamma
keywords: BDNF; Bladder; Colon; Cross-sensitization; Signal transduction