Calmodulin and calmodulin kinase II mediate emergent bursting activity in the brainstem respiratory network (preBötzinger complex)
Article first published online: 11 JAN 2013
© 2012 The Author. The Journal of Physiology © 2012 The Physiological Society
The Journal of Physiology
Volume 591, Issue 7, pages 1613–1630, April 2013
How to Cite
Mironov, S. L. (2013), Calmodulin and calmodulin kinase II mediate emergent bursting activity in the brainstem respiratory network (preBötzinger complex). The Journal of Physiology, 591: 1613–1630. doi: 10.1113/jphysiol.2012.237362
- Issue published online: 27 MAR 2013
- Article first published online: 11 JAN 2013
- Accepted manuscript online: 11 DEC 2012 10:09AM EST
- (Received 24 May 2012; accepted after revision 30 November 2012; first published online 3 December 2012)
- • Rhythmic network activity can be controlled by intracellular signalling pathways but their possible role is largely not yet elucidated.
- • This study is focused on the mechanisms of emergence and maintenance of synchronous rhythmic activity within the preBötzinger complex (preBötC), an essential part of the respiratory network in the brainstem.
- • Depression of the bursting activity by brief hypoxia and electrical stimulation correlated well with ADP-mediated inhibition of TRPM4 channels.
- • Long-lasting increases in calcium during the treatments stimulated calmodulin kinase that facilitated glutamatergic synapses and augmented rhythmic activity.
- • The results will help us better understand how respiratory rhythm is generated and how it is restored in various respiratory disorders
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.