Biology Reference
In-Depth Information
enriched in PSD. The other, consisting of the deeper region of the spine, contained a lower
density of spinophilin. No spinophilin labeling was found beyond 400 nm from the synapse
[Mully et al., 2004]. A pool of phosphorylated spinophilin was found in the spinoplasm.
Spinophilin phosphorylation by multiple kinase, in particular PKA and
CaMKII [Hsieh-
Wilson et al., 2003; Grossman et al., 2004] may modulate its localization within dendritic
spines. CaMKII is synthesized locally in dendrites and is enriched in post-synaptic fractions
enables phosphorylation of spinophilin.
Spinophilin was also found in dendrites, preterminal axons and glia suggesting that
spinophilin's role in cellular processes is not exclusive to postsynaptic functions [Mully et al.,
2004].
4.
T
HE
S
PINOPHILIN
I
NTERACTOME
Spinophilin interactome includes cytoskeletal molecules (F-actin, doublecortin,
neurabins), enzymes (like PP1), guanine nucleotide exchange factors and regulator of G-
protein signalling protein (like Lfc, kalirin-7 and RGS2), membrane receptors (D2 dopamine,
α-adrenergics, glutamatergic receptors), ions channels (TRP) and other proteins like TGN38
(Table I registered partner proteins involved in synaptic plasticity).
Shortly after the cloning of spinophilin as a novel PP1c-binding protein, another
laboratory cloned this protein based on its ability to bind to F-actin [Satoh et al., 1998].
Recombinant spinophilin and neurabin 1 interacted with each other when co-expressed in
cells. On the other hand, recombinant spinophilin was shown to form homodimers, trimers or
tetramers by interaction between coiled-coil domains. Spinophilin homomeric complexes are
thought to contribute to its actin-cross-linking activity [Satoh et al., 1998].
Doublecortin
(DCX) is a microtubule-associated protein that can induce microtubule polymerization and
stabilize microtubules filaments. Immunoprecipitation experiments with brain extracts show
that spinophilin and DCX interact in cultured cells [Tsukada et al., 2003]. DCX is one of a
number of proteins that is
required for neuronal migration in the developing cerebral cortex
[Dehmelt and Halpain, 2007].
Several studies have shown that spinophilin preferentially binds to PP1γ1 and PP1α
isoforms
in brain extracts [MacMillan et al., 1999; Terry-Lorenzo et al., 2002; Carmody et al.,
2004]. Moreover spinophilin fragments potently inhibit native PP1γ1 in vitro [Colbran et al.,
2003]. It was proposed that in vivo the PP1c/spinophilin complex exists in a dynamic
equilibrium: 1) at the “resting” state spinophilin targets and inhibits PP1c in the vicinity of its
physiological substrates, 2) in the “activating” state PP1c transiently dissociates from
spinophilin to dephosphorylate its substrates [Yan et al., 1999].
Guanine nucleotide exchange factors (GEF) and regulator of G-protein signalling (RGS)
proteins are regulators of monomeric and heteromeric G protein cycle respectively. Kalirin-7
is
a neuronal GEF for Rac1. Spinophilin, through its carboxy-terminus containing the PDZ
and coiled-coil domains interacts with kalirin-7. Neurabins target kalirin-7 to the PSD where
it could regulate dendritic morphogenesis [Penzes et al., 2001]. Lfc (Lbc[lymphoid blast
crisis]'s first cousin) is a Rho GEF that is highly expressed in neurons of the central nervous
system. The coiled-coil domain of spinophilin (and neurabin 1) interacts with that of Lfc
[Ryan et al., 2005]. Tiam1 is an ubiquitous expressed Rac-GEF and Ras-GRF1
is a
dual
