脑损伤
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Figure 2 ｜ Primary structures of Homer proteins.
The EVH1 domain can bind to the proline-rich sequence PPXXF in various proteins, such as metabotropic glutamate receptors (mGluRs), inositol trisphosphate receptors (IP3R), transient receptor potential canonical (TRPC) channels, drebrin, and dynamin3 (Hassani and Kreienkamp, 2018; Orgovan et al., 2019; Chen et al., 2020; Luo et al., 2020; Ahumada-Castro et al., 2021). In addition, the CC domain mainly mediates self-assembly or multimerization among long Homers (Figure 2) to form dimers or polymers, and the EVH1 domains of these resulting multimers then interact with other target proteins with P motifs. The presence of long Homers at the postsynaptic area thus results in the creation of diverse protein complexes, which in turn facilitate intracellular signal transduction. In contrast, short Homers lack the carboxy-terminal domains required to form multimers, but tend to compete by interacting with the target proteins of long Homers via their EVH1 domains. For instance, the first-discovered Homer protein, Homer1a, is a short-type Homer that disrupts the clustering of postsynaptic molecules mediated by long Homers and plays a dominantnegative role in regulating related signaling pathways (Table 1). Moreover, Lzip motifs are also involved in the multimerization of Homer1c, mGluR1, and N-methyl-D-aspartate (NMDA) receptors (NMDARs) (Osmankovic et al., 2018).
Figure 3 ｜ Homer signaling underlying physiological and pathological states.
Protein function is determined by its structure. Homer-related signaling depends largely on upstream and downstream signaling by target proteins that bind to Homer proteins. We classified Homer-associated signaling into three categories: glutamate receptor signaling, calcium signaling, and dendritic spine morphogenesis signaling. These three types of signaling are inter-related (Figure 3), and are closely involved in secondary brain damage after ischemic and traumatic insults. For example, glutamate receptor signaling contributes to the formation of brain edema after cerebral ischemia (Shi et al., 2017; Sladojevic et al., 2020); calcium signaling plays an important role in TBI-induced inflammation (Wofford et al., 2019); and dendritic spine morphogenesis is a key factor in neurite outgrowth and synapse recovery following ischemic and traumatic insults (Yang et al., 2020; Zhao et al., 2021). Homer proteins can thus have major impacts on these types of damage via regulation of the associated signaling pathways.