The role of resurgent currents in inherited pain syndromes
Nociceptors are nerve cells that sense potentially harmful stimuli and report to the brain and the spinal cord to effect an appropriate defense response. The reporting is relayed in the form of action potentials transmitted by voltage-gated sodium channels on these nerve cells. Interestingly, the nerve cells can be rendered hyper-excitable by various mutations in the SCN9A gene that encode the sodium channel subtype Nav1.7. As a result, two distinct types of inherited pain syndromes can arise: inherited or primary erythromelalgia, called IEM for short, and paroxysmal extreme pain disorder, or PEPD.
To date, IEM has been linked to at least 20 mutations of the SCN9A gene, all of which reduce the depolarizing potential needed to activate the mutant channel, thus facilitating hyperexcitability of the nerve cell. Consequently, seemingly innocuous activities such as exercise can trigger episodes of excruciating pain.
PEPD, on the other hand, has been linked to 10 (and potentially more) separate mutations, also on the SCN9A gene, all of which obstruct channel closure by inducing a depolarizing shift of steady-state inactivation. The result is, again, a hyperactive nerve cell causing debilitating pain.
The apparent dichotomy between IEM mutations affecting activation and PEPD mutations affecting inactivation of the sodium channels recently has been challenged after the characterization of a new mutation of the SCN9A gene published in The Journal of Biological Chemistry by Mirjam Eberhardt and collaborators in Germany.
The study highlights the case of a 22-year-old female suffering from canonical symptoms of IEM. Sequencing her SCN9A gene identified the responsible mutation, A1632T. However, instead of affecting activation of Nav1.7 as expected, the mutation, when tested in transfected human embryonic kidney cells, shifted steady-state fast inactivation to depolarizing potentials – a phenomenon expected from PEPD mutations.
This surprising result led Eberhardt and her team to determine what bifurcates pain syndrome from SCN9A mutations into IEM or PEPD. To do so, the team took advantage of a previously characterized mutation of SCN9A gene, A1632E. Interestingly, that mutation gives rise to overlapping symptoms of IEM and PEPD, displaying shift of voltage-dependence for both activation and fast inactivation.
Using whole-cell voltage-clamp recordings of human embryonic kidney cells transfected with mutant versions of the SCN9A gene, the team determined that the difference in electrophysiology between A1632E and A1632T was in the decay time constants of the current. While A1632T and wild type had similar decay constants, A1632E had a slower current decay. Based on this observation, the team hypothesized that the slower current decay also would lead to resurgent currents in the system.
Resurgent currents, an unusual phenomenon in which sodium channels briefly open during depolarizing currents in the decaying phase of an action potential, arise as a result of occlusion of the sodium channel during inactivation by a blocking particle, which is different from the intracellular loop responsible for routine channel inactivation. Thus, to test the hypothesis that A1632E mutation led to an increase in resurgent currents, the team added a peptide with the sequence of the blocking particle to the transfected cells.
They observed that resurgent currents do, indeed, increase in A1632E mutation but not in A1632T mutations. Thus they concluded that IEM results from increased inactivation of Nav1.7 without an increase in resurgent currents, while PEPD results from increased inactivation with increased resurgent currents.
The results are significant, because they offer insights into the key difference between the electrophysiology of IEM and PEPD, both of which are debilitating conditions that cause episodic pain. These findings provide a novel target area for the development of therapeutic strategies; drugs counteracting the action of the blocking particle that gives rise to resurgent currents could be developed.