Membrane Voltage Regulates Correlated Ion Channel Expression in Neurons

Post by Amanda McFarlan

What's the science?

The electrophysiological function of any given neuron is determined by the number and type of ion channels that are found in the neuron’s membrane. Neurons are able to maintain specific firing patterns by coordinating the expression of ion channels, although the underlying mechanisms of this process are still not well understood. Previous findings suggest that membrane voltage might play an important role in mediating firing patterns of neurons by providing homeostatic signals. This week in the Current Biology, Santin and Schulz investigated the role of membrane voltage in maintaining patterns of ion channel expression in the neuron.

How did they do it?

The authors began by assessing correlated mRNA expression patterns for 13 different ion channels. To do this, they dissected pyloric dilator neurons from the stomatogastric ganglion (a small motor circuit in decapod crustaceans that contains ~30 neurons each with distinct, identifiable characteristics) of adult male Jonah crabs. The mRNA expression of 13 different ion channels was quantified using single-cell PCR, followed by pairwise comparison in expression patterns between each of the 13 channels and every other channel. The first experiment had two conditions: control and silent. In the control condition, pyloric dilator neurons remained intact in their normal environment within the stomatogastric ganglion. In the silent condition, incubation in tetrodotoxin (sodium channel blocker) and the transection of the stomatogastric nerve (provides neuromodulatory inputs to the stomatostatic ganglion) resulted in pyloric dilator neurons that were deprived of all neural activity, synaptic input and neuromodulation.

In a second experiment, the authors investigated whether membrane voltage was important for maintaining correlated mRNA expression patterns of different ion channels. They measured mRNA expression levels in isolated pyloric dilator neurons for 8 hours under one of three conditions: control, silent or rescued. The control and silent conditions were the same as in the first experiment. In the rescued condition, pyloric dilator neurons were deprived from all synaptic input and neuromodulation as in the silent condition, however, the membrane potential was artificially restored to its original activity pattern by using a two-electrode voltage clamp. The authors used pairwise comparisons to assess mRNA expression pattern correlations across conditions.

What did they find?

The authors used pairwise comparisons to determine the relationship between mRNA expression levels in 13 ion channels. They showed that in the control group, 33 ion channel combinations (out of a possible 78 pairs of channels) had correlated patterns of mRNA expression. In the silent condition, they found a reduced correlation between mRNA expression levels among the 13 ion different ion channels, suggesting that neural activity, synaptic input and neuromodulation may play a critical role in regulating correlated expression of ion channel mRNA.

Next, the authors determined that 21 of the 33 pairs of ion channels with correlated mRNA expression patterns were shown to be significantly correlated in the control and rescued conditions, but not the silent condition, suggesting that the relationships between these ion channels are dependent on membrane voltage. The authors showed that in 4 out of 33 ion channel relationships, mRNA expression  correlations were present only in the control group. This finding suggests that these relationships were dependent on neuromodulatory feedback, rather than neural activity, since neuromodulatory inputs were not present in the silent or rescued conditions. Eight out of 33 ion channel interactions were unchanged across experimental groups, suggesting that they are not dependent on membrane voltage or neuromodulatory inputs. Finally, they found 5 new channel relationships that only appeared in the silent condition, suggesting that normal activity can not only influence relationships to form, but also suppress other interactions. Altogether, these findings suggest that membrane voltage may be an important factor in determining the correlation of ion channel expression.

What's the impact?

This is the first study to show that membrane voltage plays an important role in regulating mRNA expression patterns of ion channels, using a pyloric dilator neuron model. The authors also demonstrated that some ion channels have mRNA expression patterns that were not dependent on membrane voltage, which suggests that other mechanisms may be involved. Altogether, the direct link between ion channel activity and membrane voltage provides an important starting point for addressing other unanswered questions about ion channel activity patterns.  

Santin and Schulz. Membrane Voltage is a Direct Feedback Signal that Influences Correlated Ion Channel Expression in Neurons. Current Biology (2019). Access the original scientific publication here.