Homer proteins regulate signal transduction, generation of synapses and receptor trafficking. The homer protein family is comprised of three members with each member alternatively spliced to long and short forms. All members of the Homer family are synaptic scaffolding proteins with an N-terminal EVH (Ena/VASP homology 1) and a C-terminal coiled-coil domain. Long forms of the protein contain both EVH1 and coiled-coil domains and are constitutively expressed, whereas the short forms contain only the EVH1 domain and are expressed in an activity dependent manner¹.

The long form of Homer1 assembles group 1 metabotropic glutamate receptors mGluR1 and mGluR5 in large macromolecular complexes at synapses as well as with components of the NMDA receptor complex at the neuronal cell membrane. In contrast, the short form of Homer1 lacks the ability of linking mGluR1/5 to synaptic proteins and functions as an endogenous negative modulator of the mGluR1/5-inositol 1,4,5-trisphosphate receptor signaling complex. Transgenic mice with overexpressed Homer1 in striatal medium spiny neurons demonstrate normal development of striatal structure and afferent/efferent connectivity. However, motor performance in behavioral tasks and striatal responses to the psychomotor stimulant amphetamine are significantly altered in these mice².

At concentrations <200 nM of ryanodine, long and short forms of Homer1 enhance specific ryanodine binding to Ryanodine receptor 1 (RyR1). Interestingly, at larger concentrations both forms completely inhibit ryanodine binding to its receptor. Combinations of the two forms act in an additive manner to enhance or inhibit ryanodine binding activity³.