KININOGEN REGULATION AND FUNCTION IN MULTIPLE SCLEROSIS: NOVEL INSIGHTS INTO THE KALLIKREIN-KININ SYSTEM

Multiple Sclerosis (MS) is a chronic inflammatory disease of the central nervous system
(CNS) characterized by neurodegeneration and impaired neuronal excitability. Recent
studies demonstrated that voltage-gated potassium channels like K_v7.2 and K_v7.3 were
transiently upregulated during inflammatory demyelination in MS patients. These
channels generate a hyperpolarizing outward current known as the M-current. This
current activates at membrane potential below the action potential (AP) threshold,
depends on phosphatidylinositol-4,5-bisphosphate (PIP₂) for activation and effectively
limits neuronal firing. Additional pathophysiological contributory in MS derives from
components of the kallikrein-kinin system (KKS). While coagulation factor XII,
prekallikrein and bradykinin have been investigated in the context of MS before, the
aim of our study was to explore the potential role and biological regulation of kininogen
in the disease course.
In this study we demonstrated by electrophysiological recordings that focal injection of
kininogen into the auditory cortex (Au1) of mice limits neuronal activity. Further voltage
clamp experiments indicated that kininogen application reduces K_v7 channel activity in
different expression systems. In addition, the reducing effect of kininogen on neuronal
firing was prevented by intracellular application of PIP₂ in brain slices, thereby
establishing a novel link between this nonenzymatic protein and electrogenesis in
neurons and pointing to a new potential treatment axis in neuroinflammation.