Voltage-gated potassium channels (Kv channels) are
ion channels, openings of which provide an outward flow of
potassium ions repolarising the cell. In neurons, Kv channels play a crucial role in action potential repolarisation and in shaping neuronal excitability. In non-excitable cells, such as T lymphocytes, Kv channels and
calcium-activated K+ channels (KCa channels) determine the driving force for Ca2+ entry. During T cell activation the
calcium entry depolarises the cell and increases the cytosolic
calcium concentration, which in return activates Kv and KCa channels. K+ channel opening repolarises the cell and drives the membrane potential to a negative voltage. The roles of Kv channels in nervous and immune systems have been investigated here by means of a rat experimental
autoimmune disease of the central nervous system, the
experimental autoimmune encephalomyelitis (EAE). EAE is characterised clinically by
paralysis, and pathologically by inflammatory cell infiltrations into the brain and the spinal cord. Among the inflammatory cells, T lymphocytes play a major role. Hence, EAE can be adoptively transferred into syngenic animals by the injection of T cells reactive to myelin
antigens. During adoptive-EAE, somato-sensory evoked potentials recorded along the spinal tracts decrease in amplitude and axonal propagation is disrupted. We have analysed the consequences of Kv channels blockade by peptidyl toxins on central nerve conduction, on T cell activation and on the time course of EAE. In rat optic nerves, Kv channels have been identified up from postnatal day 1. Their blockade by
kaliotoxin (a
scorpion toxin) or by
dendrotoxin-I (a
snake toxin) enlarges the compound action potentials, demonstrating the participation of Kv channels to spike repolarisation. This effect disappears at adult age due to the sequestration of Kv channels under the myelin, in the paranodal regions. During acute
demyelination by lysophosphatidyl-
choline, the surface area of compound action potential decreased probably because conduction block occurred.
Demyelination unmasked Kv channels, which are again accessible to toxins. Their blockade by
dendrotoxin-I or
kaliotoxin favoured a slow delayed conduction suggesting that those Kv channel blockers exert a neurological benefit during
demyelinating diseases. In a T-cell line reactive to
myelin basic protein antigen, which is used to adoptively transfer
experimental autoimmune encephalomyelitis, Kv1.3 channels are constitutively expressed. Their blockade leads to a pronounced reduction of the T cell proliferative response,
cytokine production and Ca2+ influx. In the rat, blockade of Kv1.3 inhibits the delayed type
hypersensitivity response to
myelin basic protein prevents and treats adoptive
experimental autoimmune encephalomyelitis. Blockade of Kv channels alone or in combination with KCa channels improves the symptoms of the disease. These results demonstrate that K+ channel blockers displaying high selectivity are potent
immunosuppressive agents with beneficial symptomatic effects in
experimental autoimmune encephalomyelitis.