Abstract/Summary
Examining the mechanistic interactions between K channels’ dysfunction in rNLS8 mice. Clinical
Relevance: Current amyotrophic lateral sclerosis (ALS) treatments only produce modest
increases in lifespan and little-to-no symptom relief. As motoneuron (MN) excitability dysfunction
is an early and persistent feature of ALS, it is believed to contribute to MN degeneration. Pilot
data from the parent grant indicates key roles for Kv2.1 and SK channels in MN excitability
dysfunction. Both channels are colocalized, are commonly activated by Ca, receive common input
from C-boutons, and, importantly, mediate K ion currents. These traits, and our pilot data, suggest
a functional interaction between SK and Kv2.1 channels. The objective of this research is to
identify and characterize previously unknown interactions between Kv2.1 and SK channels. We
will study these in both normal and dysfunctional conditions, using the rNLS8 mouse model of
ALS. Rationale: These channels both regulate excitability and are altered in ALS, and are thus
likely involved in dysregulation of excitability in ALS. SK and Kv2.1 have been studied separately,
and few studies examine Kv2.1 in the spinal cord. Given their roles in excitability regulation, it is
critical that we characterize these overlooked channel interactions and their roles in ALS,
which will expand the parent grant’s results. Thus, our Supplement Specific Aims are to test the
interdependence of these K channels’ activation in healthy vs rNLS8 MNs. Functional
dependencies of either channel on the other in health would represent novel mechanistic
knowledge. Moreover, a change in these interactions within the disease model would also
represent novel mechanisms which would become novel candidates for therapeutic targets.
Completion of these studies will elucidate the mechanisms of Kv2.1 and SK dysfunctions in ALS.
