A comprehensive study of the voltage gated potassium channel Kv4.3: from functional analysis to molecular dynamics modelling

Over 100 billion neurons, connected by thousands of synapses, form the human brain. This complex neuronal network allows us to perform cognitive and motor tasks, such as thinking, talking, feeling and moving our arms and legs. Specialized proteins, known as ion channels, make it possible for neurons to communicate with each other by generating electrical stimuli. When ion channels do not work properly due to mutations, people suffer from various disorders, known as channelopathies. Mutations in the Kv4.3 channel cause motor disorders (ataxia), in some cases, accompanied by other clinical conditions, such as intellectual disability and epilepsy. Patients suffering from this disorder have difficulties in performing daily motor tasks, such as standing upright and grabbing objects. In neuronal cells, the Kv4.3 channel generates an electrical current which ‘filters’ incoming electrical stimuli and allows correct neuronal communication. In this thesis, we have studied the effect of mutations found in patients on the Kv4.3 channel activity, and we have developed and used different state of the-art technologies to understand how the Kv4.3 channel works. We found that disease causing mutations reduce the activity of the Kv4.3 channel. Our research has provided new information that brings us closer to the understanding of complex neurological disorders linked to the malfunctioning of the Kv4.3 channel