8.A.29 The Homer1 (Homer1) Family of Excitation-Contraction Coupling Proteins
The Homer family of scaffolding proteins consists of three members, Homer1, Homer2, and Homer3, and several splice variants. The Homers are typified by an N-terminal Ena/VASP homology 1 (EVH) domain and C-terminal coiled coil and leucine zipper domains. The latter (residues 170-330) are similar in sequence to two repeats in the LetM1 protein (TC# 8.A.20.1.1). The EVH domain is a protein-protein binding module that recognizes the proline-rich motifs PPXXF, PPXF, and LPSSP , whereas the coiled coil domain and leucine zippers serve to multimerize the Homers into scaffolds that assemble signaling proteins into complexes. The Homer1 gene is unique in that it codes for the short Homer1a (H1a) and a long Homer1b/c (H1b/c). H1a lacks the coiled coil domain and leucine zipper, and it antagonizes the functions of the multimerizing Homers by dissociating the complexes formed by them.
Many Ca2+ signaling proteins express Homer binding sequences, including G protein-coupled receptors, plasma membrane Ca2+ ATPase pumps, IP3 receptors, canonical transient receptor potential (TRPC) channels, and notably, the ryanodine receptors (RyRs) and the α1C subunit of Cav1.2 and α1D subunit of Cav1.3 L-type Ca2+ channels. The Homers recruit the Ca2+ signaling proteins to the plasma membrane and cellular microdomains, such as dendritic spines, but are not essential for assembly or retention of the complexes, because deletion of the Homers does not affect localization of the complexes. On the other hand, the Homers modulate the efficiency and intensity of Ca2+ signaling by negatively regulating the activity of proteins within the Ca2+ signaling complex (Huang et al, 2007).
Another important function of Homer1 is the mediation of the conformational coupling between IP3Rs and TRPC channels. Thus, Homer1 binds TRPC channels and the IP3Rs to allow the gating of TRPC channels by IP3Rs. This form of coupling is reminiscent of excitation-contraction (E-C) coupling in muscle, which is mediated by the sarcolemmal voltage-activated L-type Ca2+ channels and the RyRs Ca2+ release channels in the sarcoplasmic reticulum. Homer1 may play a role in E-C coupling. Homer 1 functions as an important scaffold for TRP channels and regulates mechanotransduction in skeletal muscle (Stiber et al., 2008).
Excitation-contraction (E-C) coupling and Ca2+-induced Ca2+ release in smooth and cardiac muscles is mediated by the L-type Ca2+ channel isoform Cav1.2 and the ryanodine receptor isoform RyR2. Although physical coupling between Cav1.1 and RyR1 in skeletal muscle is well established, it is generally assumed that Cav1.2 and RyR2 do not directly communicate either passively or dynamically during E-C coupling. Homer1 mediates dynamic interaction between Cav1.2 and RyR2. H1a and H1b/c reciprocally modulates a dynamic interaction between Cav1.2 and RyR2 to regulate the intensity of Ca2+-induced Ca2+ release and its dependence on membrane depolarization. A 'two-state' model of E-C coupling by Cav1.2 and RyR2 suggests that in one state, Cav1.2 couples to RyR2 by H1b/c, which results in reduced responsiveness to membrane depolarization and in the other state, H1a uncouples Cav1.2 and RyR2 to enhance responsiveness to membrane depolarization (Huang et al., 2007).