title: Calmodulin and calmodulin kinase II mediate emergent bursting activity in the brainstem respiratory network (preBötzinger complex).
abstract: Emergence of persistent activity in networks can be controlled by intracellular signalling pathways but the mechanisms involved and their role are not yet fully explored. Using calcium imaging and patch-clamp we examined the rhythmic activity in the preBötzinger complex (preBötC) in the lower brainstem that generates the respiratory motor output. In functionally intact acute slices brief hypoxia, electrical stimulation and activation of AMPA receptors transiently depressed bursting activity which then recovered with augmentation. The effects were abrogated after chelation of intracellular calcium, blockade of L-type calcium channels and inhibition of calmodulin (CaM) and CaM kinase (CaMKII). Rhythmic calcium transients and synaptic drive currents in preBötC neurons in the organotypic slices showed similar CaM- and CaMKII-dependent responses. The stimuli increased the amplitude of spontaneous and miniature excitatory synaptic currents indicating postsynaptic changes at glutamatergic synapses. In the acute and organotypic slices, CaM stimulated and ADP inhibited calcium-dependent TRPM4 channels and CaMKII augmented synaptic drive currents. Experimental data and simulations show the role of ADP and CaMKII in the control of bursting activity and its relation to intracellular signalling. I propose that CaMKII-mediated facilitation of glutamatergic transmission strengthens emergent synchronous activity within preBötC that is then maintained by periodic surges of calcium during the bursts. This may find implications in restoration and consolidation of autonomous activity in the respiratory disorders.
authors.affiliation: Department of Neuro- and Sensory Physiology, Georg-August-University, Humboldtallee 23, 37073 Göttingen, Germany. smirono@gwdg.de
authors.forename: S L
authors.initials: SL
authors.lastname: Mironov
mesh_terms: D000244:Adenosine Diphosphate / Q000502:physiology; D000818:Animals; D001933:Brain Stem / Q000502:physiology*; D002118:Calcium / Q000502:physiology; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000502:physiology*; D002147:Calmodulin / Q000502:physiology*; D004558:Electric Stimulation; D000860:Hypoxia / Q000503:physiopathology; D051379:Mice; D009474:Neurons / Q000502:physiology; D018408:Patch-Clamp Techniques; D010507:Periodicity; D050053:TRPM Cation Channels / Q000502:physiology
chemical_list: D002147:Calmodulin; D050053:TRPM Cation Channels; C476766:TRPM4 protein, mouse; D000244:Adenosine Diphosphate; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D002118:Calcium