Kalirin and Trio: RhoGEFs in Synaptic Transmission, Plasticity, and Complex Brain Disorders

Abstract

Changes in the actin cytoskeleton are a primary mechanism mediating the morphological and functional plasticity that underlies learning and memory. The synaptic Ras homologous (Rho) guanine nucleotide exchange factors (GEFs) Kalirin and Trio have emerged as central regulators of actin dynamics at the synapse. The increased attention surrounding Kalirin and Trio stems from the growing evidence for their roles in the etiology of a wide range of neurodevelopmental and neurodegenerative disorders. In this Review, we discuss recent findings revealing the unique and diverse functions of these paralog proteins in neurodevelopment, excitatory synaptic transmission, and plasticity. We additionally survey the growing literature implicating these proteins in various neurological disorders.

Keywords: Kalirin; RhoGEF; actin; autism; neurodegeneration; neurotransmission; schizophrenia; synaptic plasticity; trio.

Figure 1.. Major Trio and Kalirin isoforms.

Alternative splicing of Kalirin and Trio genes gives rise to numerous isoforms. This alignment displays the dominant Trio and Kalirin species, along with the Drosophila (dTrio, row 5) and C. elegans orthologs (UNC-73, row 4). Kalirin and Trio contain two guanine nucleotide exchange factors (GEFs) that are composed of a catalytic Dbl homology domain, and a pleckstrin homology domain that functions allosterically. GEF1 activates Rac1 and RhoG, whereas GEF2 activates RhoA. Kalirin and Trio GEFs are well conserved, with the greatest sequence diversity observed in their non-GEF flanking sequences. Kalirin-7 and Trio-9 are the dominant species in the brain. Kalirin-7 is unique in that it harbors a C-terminal PDZ-ligand. Alternative start sites in exon 1 of Kalrn generate Kalirin-7 with various N-terminal sequences (so called a, b, c, and d-front Kalirin-7). For further structural highlights, see Box 1. Abbreviations: SH3, Src homology 3; FnIII, Fibronectin type III; Ig, Immunoglobulin; GEF, Guanine nucleotide exchange factor; PDZ, Postsynaptic density-95/discs large/zona occludens.

Figure 2, Key Figure.. Kalirin and Trio serve postsynaptic and presynaptic functions.

Kalirin and Trio interact with multiple proteins at the pre- and post-synaptic sites. These interactions integrate upstream signals into dynamic changes in the actin cytoskeleton that work to regulate spine formation, dendritic morphology, and presynaptic release. Kalirin-7 interacts with several neurotransmitter receptors and adhesion molecules, translating glutamate-mediated signals and synaptic adhesion into changes in the actin cytoskeleton. Presynaptically, Trio interacts with many proteins involved in vesicle release and trafficking, regulating the actin dynamics facilitating these processes. Upstream signaling regulating Trio at postsynaptic spines and Kalirin at the presynaptic site is less understood. Abbreviations: Glu, Glutamate; Cbln1, Cerebellin-1; NMDAR, N-methyl-D-aspartate receptor; AMPAR, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor; LAR, LCA-related protein tyrosine phosphatase; PDZ, Postsynaptic density-95/discs large/zona occludens; CaMKII, Ca2+/calmodulin-dependent protein kinase II; EphB2, EPH receptor B2; CASK, calcium/calmodulin dependent serine protein kinase; RIM, Rab interacting molecule; ELKS, ERC/RAB6-interacting/CAST; MINT, Munc18 interacting protein; Trk, Tropomyosin receptor kinase; Rac1, Ras-related C3 botulinum toxin substrate 1; GTP, Guanosine triphosphate; GDP, Guanosine diphosphate.

Figure 3:. Disease-related mutations in Trio and Kalirin.

Mutations in Trio are associated with several neurological disorders. A majority of ASD/ID mutations occur in the first GEF domain, with an additional hotspot located in the second to last spectrin repeat. The top Trio row depicts missense mutations, the second and third rows depict nonsense mutations and copy number variants. The Asterix indicates a premature stop codon. Fewer disease-associated mutations have been identified in Kalirin. Abbreviations: DH, Dbl homology; PH, Pleckstrin homology; SH3, Src homology 3; FnIII, Fibronectin type III; IG, Immunoglobulin; GEF, Guanine nucleotide exchange factor; PDZ, Postsynaptic density-95/discs large/zona occludens.