Homer protein family regulation in skeletal muscle and neuromuscular adaptation.

Scaffolding adaptor proteins of the Homer family have recently been implicated in regulation of a large number of physiological processes owing to their remarkable ability to coordinate a complex network of different molecular players within the same signaling pathway. However, because of their unique molecular properties that also allow functional modulation of a plethora of different interacting protein partners, Homers seem to play additional and important roles in the integration of several molecular players belonging to different signaling pathways and thus allowing crosstalk. The role of the Homer protein family has been previously extensively investigated in neuronal tissue where it was first discovered as a new protein family being upregulated in response to brain seizures (Brakeman P.R., et al., Nature 1997, 386, 284-288.). Recently, the role of Homers was also proposed in skeletal muscle physiology. For instance, it has been shown that Homers regulate both the myogenic differentiation program and the open probability (Po) of several ion channels. Furthermore, by knocking out Homer1, one of the three Homer genes, mice carrying such deletion displayed a pronounced skeletal muscle myopathy associated with altered transient receptor potential activity and calcium homeostasis. Homer expression has now been further characterized at the neuromuscular junction in skeletal muscle. Apart from their known role at central synapses, Homers are important physiological determinants in differentiation, development, and adaptation in skeletal muscle and the neuromuscular system and thus integrating motor neuron control, for example, with downstream calcium signaling pathways in muscle fibers.