Stable and efficient synaptic transmission depends largely on the maintenance of a high number/density of postsynaptic receptors at synaptic sites. At the neuromuscular junction (NMJ), the synapse between spinal motor neurons and skeletal muscle cells, the mechanisms that regulate the stability of postsynaptic nicotinic acetylcholine receptors (AChRs) over the lifetime of animals remain largely unknown. Recent studies from our lab showed that ?kap, a non-kinase muscle anchoring protein encoded within the calcium/calmodulin kinase II ? gene, plays an important role in regulating the stability of nicotinic acetylcholine receptors (AChRs) by the ubiquitin-proteasome dependent mechanism. In view of these results, we propose in the first aim to investigate the effect of ?kap knockdown on the formation, maturation, and maintenance of healthy NMJs. In the second aim we propose to investigate the effect of ?kap gain-of-function during the maturation and maintenance of compromised NMJs deficient in ?-syntrophin. In the third aim we propose to investigate the link between ?-dystrobrevin/ ?kap/ the deubiquitinating protease USP9X and AChR stability in developing and mature synapses of mice deficient in ?dbn. The outcomes of these studies will be relevant for many neuromuscular diseases where the number and density of AChRs are compromised.
The efficiency of synaptic transmission relies on the maintenance of a high number of receptors at the postsynaptic membrane. Despite decades of research, it is still not well understood how the stability of postsynaptic receptor density is maintained and regulated in living animals. Recent work from our lab showed that muscle calmodulin kinase II-related anchoring protein (?kap) has a profound effect on the stability of acetylcholine receptors in cultured muscle cells and in living animal. This proposal will explore the role of ?kap in the formation, maturation and maintenance of healthy and compromised neuromuscular synapses on muscles of living mice. These studies will add to our understanding of the basic mechanisms that underlie the stability of receptors and will be relevant to developing new approaches for treating neurological diseases where the number of receptors is compromised.
