Biology Reference
In-Depth Information
exchange factor for both Ras and Rac. They both interact through their amino-terminal region
with spinophilin [Buchsbaum et al., 2003].
The sequence spanning the PDZ and coiled-coil
domains of spinophilin (amino acids 444-817) was shown to be implicated in interaction with
Tiam1. RGS proteins play a crucial role in the shutting off process of G-protein-mediated
responses and can be divided into five subfamilies [Ishii and Kurachi, 2003]. Spinophilin (and
neurabin 1) binds to different members of the RGS familly (RGS1, RGS2, RGS4, RGS16 and
GAIP) [Wang et al., 2007]. The binding between spinophilin and RGS2 occurs through the
amino acids residues 480 to 525 of the scaffold protein and the amino-terminal domain of the
RGS [Wang et al., 2005].
Spinophilin interacts with the D2 dopamin and α-adrenergic receptors (AR), that belong
to the family of seven-transmembrane domain receptors, and with the ionotropic NMDA and
AMPA-type glutamate receptors. Using the 3i of the D2 dopamine receptor, spinophilin (and
not neurabin 1) was identified as a protein that specifically associates with the receptor in rat
hippocampal [Smith et al., 1999]. The 3i of the α
2A-
AR, α
2B-
AR, and α
2C-
AR subtypes
interacted with spinophilin (and not neurabin 1). Furthermore, interactions occur in intact
cells in an agonist-regulated fashion [Richman et al., 2001]. Sequences at the extreme amino-
terminal and carboxy-terminal ends of the 3i are critical for interaction with spinophilin.
Recently, it was shown that α
1B
-AR can interact with spinophilin in vitro [Wang et al., 2005].
Moreover, spinophilin (but not neurabin 1) binds to the 3i of cholecystokinin (CCK) A,
CCKB and M3 muscarinic receptors [Wang et al., 2007]. Both spinophilin and neurabin 1
PDZ domains directly bind to GluR2-, GluR3- (AMPA receptor) and NR1C2'-, NR2A/B-
and NR2C/D- (NMDA receptor) derived peptides [Kelker et al., 2007].
The transient receptor potential canonical (TRPC) ion channels are Ca
2+
/cation selective
channels that are highly expressed in the central nervous system. Spinophilin was identified
with other dendritic spines proteins as a protein partner of TRPC5 and TRPC6 channels [Goel
et al., 2005]. TGN38 is an integral membrane protein that constitutively cycles between the
trans-Golgi network (TGN) and plasma membrane via endosomal intermediates. TGN38
directly interacts with the coiled-coil region of spinophilin (and neurabin 1), preferentially
with dimerized neurabins [Stephens and Banting, 1999].
5.
S
YNAPTIC
P
LASTICITY
Excitatory synapses are localized on dendritic spines. In these protusions of the dendrites,
F-actin is enriched in the vicinity of the PSD. Rearrangements of the spine's actin
cytoskeleton are associated with synaptic transmission and plasticity. The Rho family of
small GTPases are key regulators of the F-actin cytoskeleton and are involved in regulating
the morphology of dendritic spines. The molecular mechanism that controls spine
morphology was in part recently elucidated and involved Lfc a binding partner of neurabins
[for a detailed discussion see Sarrouilhe et al., 2006]. The Rho-GEF Lfc is an upstream
regulator that activates Rho through the exchange of bound GDP for GTP [Ryan et al., 2005].
Furthermore, phosphorylation by CaMKII, PKA and ERK2 reduced the affinity of
spinophilin for F-actin and thus, could regulate spinophilin ability to reorganize actin
cytoskeleton in spines [Hsieh-Wilson et al., 2003; Grossman et al., 2004; Futter et al., 2005].
Spinophilin and neurabin 1 represented two major PP1c-binding proteins concentrated in PSD
