Actin Isoforms in Neuronal Development and Function - International Review of Cell and Molecular Biology - page 166

the nucleotide coding sequences between β- and γ-actin resulted in a more
complex RNA secondary structure for γ-actin and slowing its translation
rate ( Zhang et al., 2010 ). The reduced translation speed of γ-actin is suf-
ficient to allow a lysine residue normally rapidly buried within the actin
molecule to be exposed and ubiquitinated, leading to its rapid degradation
and likely explaining why arginylated γ-actin was not previously detected.
The role of arginylation and specifically the arginylation of actin isoforms
is only beginning to be explored, with essentially nothing known regard-
ing its role in neuronal development and function. A whole body Ate1 KO
mouse is embryonic lethal due to profound angiogenic remodeling and
developmental heart defects ( Kwon et al., 2002 ). However, generation of
a conditional Ate1 KO mouse through the use of a tamoxifen-inducible
Cre system in adult animals did reveal important roles for arginylation and
potentially the arginylation of β-actin in the nervous system ( Brower and
Varshavsky, 2009 ). In addition to being significantly smaller than control lit-
termates, conditional adult Ate1 KO mice had proportionally larger brains
and exhibited profound hyperactivity in open-field behavioral assays. These
mice also presented with seizures and an enhanced startle response suggest-
ing heightened anxiety levels. Finally, core body temperature was also abnor-
mal, which could have potential links to hypothalamic dysfunction. Notably,
small size, potential hypothalamus defects, and profound hyperactivity are
phenotypes shared with a CNS-specific β-actin KO mouse ( Cheever et al.,
2012 ), potentially linking some of these phenotypes to the specific arginyl-
ation of β-actin within neurons and the nervous system.
While the differential fates of arginylated cytoplasmic actins are likely
based on nucleotide coding sequences, there is still the potential for dis-
tinct interactions between the cytoplasmic actins and actin-binding pro-
teins, which could have significant implications for actin isoform function.
Importantly, the four divergent amino acids between β- and γ-actin are
exposed on the outer surface of actin filaments where they could poten-
tially interact differentially with actin-binding proteins ( Fujii et al., 2010 ;
Oda et al., 2009 ). In addition, antibodies capable of distinguishing between
β- and γ-actin have been generated by multiple groups ( Gimona et al.,
1994 ; Hanft et al., 2006 ; Otey et al., 1986 ; Perrin et al., 2010 ; Sonnemann
et al., 2006 ), providing even more support for the possibility of proteins
distinguishing the subtle differences between β- and γ-actin.Yet despite this
data, there has been no definitive evidence to date supporting differential
interactions of an actin-binding protein with a specific cytoplasmic actin
isoform. It is worth noting however that a small number of studies have