Channeling the Central Dogma

Abstract

How do neurons and networks achieve their characteristic electrical activity, regulate this activity homeostatically, and yet show population variability in expression? O'Leary et al. address some of these thorny questions in this theoretical analysis that starts with the Central Dogma.

The interplay between genetic and bioelectrical signaling permits a spatial regionalisation of membrane potentials in model multicellular ensembles

“…The single-cell genetic regulation considered here is based on mean-field kinetic equations for the mRNA and protein relative concentrations. These equations could now be extended to more complex genetic networks 41 45 and coupled to the bioelectrical description of Fig. 1 .…”

“…Figure 1 shows a simple scheme illustrating the two feedback scenarios considered for the genetic and bioelectrical descriptions together with the relevant biophysical equations. The simplest modeling of genetic regulation is based on the mean-field equations 38 39 40 41 42 43 44 45 . As to the bioelectrical regulation, we assume that a particular ion channel in the cell membrane, the voltage-gated outward-rectifying channel, is formed by a specific protein whose concentration p depends on the intracellular concentration m of the corresponding mRNA.…”

“…The highly non-linear characteristics of the equations describing genetic 38 39 40 41 42 45 and bioelectrical networks 19 22 29 suggest significant feedback scenarios. The cell potential may influence the rate of gene transcription into mRNA, eventually resulting in changes of the rate of mRNA translation into proteins that should impact in the function of the protein ion channels.…”

“…The cell potential may influence the rate of gene transcription into mRNA, eventually resulting in changes of the rate of mRNA translation into proteins that should impact in the function of the protein ion channels. The effects of the membrane potential on gene expression are indirect and mediated by the following processes which are regulated by the potential difference V between the intracellular and extracellular media: ( i ) the calcium cell entry and subsequent regulation of genetic pathways 2 5 6 , ( ii ) the transport of different signaling molecules to the cell 1 2 3 7 41 , ( iii ) the electrically-induced conformational changes in the voltage-sensing domains of membrane proteins 1 4 , and ( iv ) the activation of voltage-gated potassium 5 46 47 and calcium 2 6 24 48 49 channels. These experimental facts constitute functional links between the genetic and bioelectric descriptions, establishing clear qualitative connections between the model and experimental results.…”

Consequences of degeneracy in network function

“…They selected models that matched the electrophysiological properties of biological neurons, and found that conductance correlations were not observed. In contrast, O’Leary et al [23]** and O’Leary et al [24]** generated model neurons that did use homeostatic tuning rules and correlations were observed (also see [25]).…”