Effect of beta2-adrenergic receptor agonists on the acetylcholine receptor clustering pathway in congenital myasthenic syndromes. (360G-Wellcome-103406_Z_13_Z)

Congenital myasthenia contains a group of inherited disorders affecting neuromuscular transmission. The host laboratory has previously shown that beta2-adrenergic agonists, such as salbutamol, are particularly beneficial in a subgroup of patients with congenital myasthenia, typically involving DOK7 mutations. DOK7 is a member of the acetylcholine receptor (AChR) clustering pathway, a pathway crucial for synaptic stabilization. Currently, there is no clear insight into how salbutamol counteracts synaptic dysfunction underlying congenital myasthenia. But, clinical data together with preliminary data from the host laboratory suggest that salbutamol plays a role in synaptic stabilization, more specifically by promoting AChR clustering. This study will examine the effect of salbutamol on AChR cluster formation in cell cultures transfected with mutant DOK7, and on strength and neurotransmission in a mouse model reflecting AChR deficiency. This study will also investigate whether the second messenger system of the beta2-adrenoreceptor interferes with the AChR clustering pathway by phosphorylation of its key proteins or their transcription factors, resulting in an increase in their activity or synthesis. Increased understanding of the interaction between beta2-adrenoreceptor signaling and synaptic stabilization pathways will advance tailored drug choice in myasthenic patients and might lead to a new drug target. Findings might be transferable to central synapses.