Effects of Vesl/Homer Proteins on Intracellular Signaling

Abstract

The clustering of signaling molecules at specialized cellular sites allows cells to effectively convert extracellular signals into intracellular signals and to produce a concerted functional output with specific temporal and spatial patterns. A prime example for these molecules and their effects on cellular signaling are the postsynaptic density proteins of the central nervous system. Recently, one group of these proteins, the Vesl/Homer protein family has received increased attention because of its unique molecular properties that allow both the clustering and functional modulation of a plethora of different binding proteins. Within multiprotein signaling complexes, Vesl/Homer proteins influence proteins as diverse as metabotropic glutamate receptors; transient receptor potential channels; intra-cellular calcium channels; the scaffolding protein, Shank; small GTPases; transcription factors; and cytoskeletal proteins. Furthermore, interaction with such functionally relevant proteins also links Vesl/Homer proteins indirectly to an even larger group of cellular effector proteins, putting the Vesl/Homer proteins at the crossroads of several critical intracellular signaling processes. In addition to the initial reports of Vesl/Homer protein expression in the central nervous system, members of this protein family have now been identified in other excitable cells in various muscle types and in a large number of nonexcitable cells. The widespread expression of Vesl/Homer proteins in different organs and their functional importance in cellular protein signaling complexes is further evidenced by their conservation in organisms from Drosophila to humans.

Homer-1a immediate early gene expression correlates with better cognitive performance in aging

“…However, the involvement of Homer-1a offers a novel perspective on the mechanisms of progressive synaptic changing in aging: Homer-1a is encoded by an immediate early gene (Brakeman et al 1997;Kato et al 1998), while other splice variants encoded by the same gene are constitutively expressed scaffolding and signaling proteins (Brakeman et al 1997;Kato et al 1998;Duncan et al 2005;Hayashi et al 2009). Mechanistically, Homer-1a is thought to compete with Homer-1b/c for the physical interaction sites of the ligands of Homer-1b/c, providing a cellular mechanism for control of synaptic activity and endogenous neuroprotection (Duncan et al 2005).…”

“…Mechanistically, long Homer-1 isoforms serve as important scaffolding molecules that bring synaptic proteins into proximity (Duncan et al 2005). For instance, coupling of inositol-1,4,5-trisphosphate receptors in the membranes of the endoplasmic reticulum and metabotropic glutamate receptors at the plasma membrane generates a structural and functional signaling domain (Tu et al 1998;Mao et al 2005;Menard and Quirion 2012) (Fig.…”

“…The CC domain is absent in the Homer-1a isoform suggesting that this isoform, which is therefore incapable of multimerization, has the potential to act as a dominant negative regulator. In fact, Homer-1a competes with the long isoforms for binding sites on Homer-1 ligands, thereby providing a stimulus-dependent mechanism using the molecular determinants of Vesl/Homer proteins to regulate intracellular signaling pathways (Duncan et al 2005).…”

“…The Homer-1 gene is alternatively spliced into four known isoforms. The short isoform Vesl-1S/ Homer-1a is an immediate early gene product that is rapidly and transiently induced by high synaptic activity, including during seizures and long-term potentiation (Brakeman et al 1997;Kato et al 1998;Duncan et al 2005), while the long Homer-1 isoforms are typically expressed constitutively (Duncan et al 2005).…”

Loss of Metabotropic Glutamate Receptor-Dependent Long-Term Depression via Downregulation of mGluR5 after Status Epilepticus

“…Homer proteins are a family of Ͼ15 postsynaptic scaffolding molecules that facilitate the aggregation of specific postsynaptic proteins, and modulate their function (for review, see Duncan et al, 2005). Most Homer isoforms are constitutively expressed, have a molecular mass of ϳ47 kDa, and contain EVH1 domains that bind mGluRs, as well as CC domains that allow homodimerization and heterodimerization.…”