I thinkICAN: modulation of TRPM4 channels may contribute not only to the emergence of rhythm, but robust output and metabolic sensitivity of the preBötzinger Complex inspiratory network
Understanding the mechanisms by which central rhythm generators (CRGs) produce the neural rhythms that drive behaviours such as locomotion, chewing and breathing is a longstanding, fundamental problem that also has great clinical relevance. A topic of current debate is whether the basis of CRG function resides in the intrinsic auto-rhythmic properties of pacemaker neurons or emergent properties of the network (Del Negro & Hayes, 2008). Strong support for the latter comes from work in the preBotzinger complex (preBotC, a region critical for rhythm generation) of the inspiratory network that shows powerful functional links among AMPA receptors, Ca2+ channels, group I metabotropic glutamate receptors (mGluRs) and the TRPM4-mediated (transient receptor potential melastatin 4 subtype), burst-generating, non-specific cation current, ICAN (Mironov 2008; Pace & Del Negro, 2008). In this model, referred to as the group pacemaker hypothesis, synaptically released glutamate periodically activates AMPA and group I mGluRs. AMPA receptor-mediated depolarization evokes Ca2+ current via voltage-gated Ca2+ channels. Inositol 1,4,5-trisphosphate (IP3) receptors bind this Ca2+ as well as IP3 synthesized as a result of mGluR activation to cause regenerative intracellular Ca2+ release. Ca2+ from Ca2+ channels and intracellular stores evokes ICAN, which provides the bulk of the inward current underlying the inspiratory drive potential. Thus, the mechanism of rhythm generation in vitro emerges from the properties of a network in which latent burst-generating, intrinsic conductances are recruited by excitatory synaptic interactions among preBotC inspiratory neurons (Feldman & Del Negro, 2006; Pace & Del Negro, 2008).