title: Protein kinase G-dependent mechanisms modulate hypoglossal motoneuronal excitability and long-term facilitation.
abstract: Since protein kinase-dependent modulation of motoneuronal excitability contributes to adaptive changes in breathing, we hypothesized that cGMP-dependent pathways activating protein kinase G (PKG) modulate motoneuronal inspiratory drive currents and long-term plasticity. In a medullary slice preparation from neonatal rat (postnatal days 0-4) generating spontaneous respiratory-related rhythm, hypoglossal (XII) motoneuronal inspiratory drive currents and respiratory-related XII nerve activity were recorded. Focal application of a PKG activator, 8-bromoguanosine-3',5'-cyclomonophosphate (8-Br-cGMP), to voltage-clamped XII motoneurones decreased inspiratory drive currents. In the presence of tetrodotoxin (TTX), 8-Br-cGMP decreased the exogenous postsynaptic inward currents induced by focal application of AMPA. Intracellular dialysis of XII motoneurones with an inhibitory peptide to PKG (PKGI) increased endogenous inspiratory-drive currents and exogenous AMPA-induced currents. Application of 8-Br-cGMP with PKGI had no further effect on spontaneous or evoked currents, confirming that the observed effects were induced by PKG. However, PKG differentially increased longer-term plasticity. Three 3 min applications (separated by 5 min) of the α(1)-adrenergic agonist phenylephrine (PE) in combination with 8-Br-cGMP yielded greater in vitro long-term facilitation than PE alone. These data indicate the presence of a cGMP/PKG-dependent signalling pathway in XII motoneurones that modulates inspiratory drive currents and plasticity of XII motoneurones, possibly contributing to their adaptation during physiological challenges, such as sleep and exercise.
authors.affiliation: Department of Neurobiology, David Geffen School of Medicine at UCLA, University of California, Los Angeles, Box 951763, Los Angeles, CA 90095-1763, USA.
authors.forename: Shane A
authors.initials: SA
authors.lastname: Saywell
authors.forename: Walter E
authors.initials: WE
authors.lastname: Babiec
authors.forename: Natalia V
authors.initials: NV
authors.lastname: Neverova
authors.forename: Jack L
authors.initials: JL
authors.lastname: Feldman
mesh_terms: D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D017869:Cyclic GMP-Dependent Protein Kinases / Q000502:physiology*; D007002:Hypoglossal Nerve / Q000187:drug effects / Q000201:enzymology*; D001239:Inhalation / Q000187:drug effects / Q000502:physiology; D017774:Long-Term Potentiation / Q000187:drug effects / Q000502:physiology*; D009046:Motor Neurons / Q000187:drug effects / Q000201:enzymology*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D015124:8-Bromo Cyclic Adenosine Monophosphate; D017869:Cyclic GMP-Dependent Protein Kinases