title: HCN channels contribute to serotonergic modulation of ventral surface chemosensitive neurons and respiratory activity.
abstract: Chemosensitive neurons in the retrotrapezoid nucleus (RTN) provide a CO2/H(+)-dependent drive to breathe and function as an integration center for the respiratory network, including serotonergic raphe neurons. We recently showed that serotonergic modulation of RTN chemoreceptors involved inhibition of KCNQ channels and activation of an unknown inward current. Hyperpolarization-activated cyclic-nucleotide-gated (HCN) channels are the molecular correlate of the hyperpolarization-activated inward current (Ih) and have a high propensity for modulation by serotonin. To investigate whether HCN channels contribute to basal activity and serotonergic modulation of RTN chemoreceptors, we characterize resting activity and the effects of serotonin on RTN chemoreceptors in vitro and on respiratory activity of anesthetized rats in the presence or absence of blockers of KCNQ (XE991) and/or HCN (ZD7288, Cs(+)) channels. We found in vivo that bilateral RTN injections of ZD7288 increased respiratory activity and in vitro HCN channel blockade increased activity of RTN chemoreceptors under control conditions, but this was blunted by KCNQ channel inhibition. Furthermore, in vivo unilateral RTN injection of XE991 plus ZD7288 eliminated the serotonin response, and in vitro serotonin sensitivity was eliminated by application of XE991 and ZD7288 or SQ22536 (adenylate cyclase blocker). Serotonin-mediated activation of RTN chemoreceptors was blocked by a 5-HT7-receptor blocker and mimicked by a 5-HT7-receptor agonist. In addition, serotonin caused a depolarizing shift in the voltage-dependent activation of Ih. These results suggest that HCN channels contribute to resting chemoreceptor activity and that serotonin activates RTN chemoreceptors and breathing in part by a 5-HT7 receptor-dependent mechanism and downstream activation of Ih.
authors.affiliation: Department of Physiology and Neurobiology, University of Connecticut, Storrs, Connecticut;
authors.forename: Virginia E
authors.initials: VE
authors.lastname: Hawkins
authors.affiliation: Department of Physiology and Neurobiology, University of Connecticut, Storrs, Connecticut;
authors.forename: Joanna M
authors.initials: JM
authors.lastname: Hawryluk
authors.affiliation: Department of Pharmacology, University of Sao Paulo, Sao Paulo, Brazil; and.
authors.forename: Ana C
authors.initials: AC
authors.lastname: Takakura
authors.affiliation: Department of Physiology and Neurobiology, University of Connecticut, Storrs, Connecticut;
authors.forename: Anastasios V
authors.initials: AV
authors.lastname: Tzingounis
authors.affiliation: Department of Physiology and Biophysics, University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: Thiago S
authors.initials: TS
authors.lastname: Moreira
authors.affiliation: Department of Physiology and Neurobiology, University of Connecticut, Storrs, Connecticut; Daniel.mulkey@uconn.edu.
authors.forename: Daniel K
authors.initials: DK
authors.lastname: Mulkey
mesh_terms: D000200:Action Potentials; D000067956:Adenylyl Cyclase Inhibitors; D000818:Animals; D001933:Brain Stem / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D002586:Cesium / Q000494:pharmacology; D002628:Chemoreceptor Cells / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D026902:Potassium Channel Blockers / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012119:Respiration; D059326:Serotonergic Neurons / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D012701:Serotonin / Q000494:pharmacology
chemical_list: D000067956:Adenylyl Cyclase Inhibitors; D064428:Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels; D026902:Potassium Channel Blockers; D011743:Pyrimidines; C082246:ICI D2788; D002586:Cesium; D012701:Serotonin
keywords: 5-HT7; Gs-coupled receptor; cAMP; retrotrapezoid nucleus; serotonin