Cupidin is an isoform of Homer/Vesl that links Gq-coupled mGluRs to the actin cytoskeleton in mouse cerebellar granule cells (Shiraishi etal. 1999). The N-terminal domain of Cupidin binds to the C-terminal tail of mGluRs and also interacts with actin. The C-terminal portion of Cupidin binds Cdc42, a member of the Rho family of small GTPases, in a GTP-dependent manner. Thus Cupidin serves as a post-synaptic scaffold protein linking mGluRs to both the actin cytoskeleton and Rho proteins, and also suggests that Cupidin may be involved in the dynamic morphological changes that occur during synapse formation or plasticity in neuron.
PICK1 (protein interacting with C fcinase) is a PDZ-containing protein that binds to mGluR7a, a presynaptic autoreceptor (Boudin et al. 2000). Coexpression of PICK1 and mGluR7a in heterologous expression systems results in the aggregation ofmGluR7a. In addition, PICK1 causes a reduction in PKCa-evoked phosphorylation of mGluR7a in in vitro phosphorylation assays (Dev etal. 2000) and thus modulates the desensitization ofmGluR7a responses. Interestingly, calmodulin (CaM) and Gßy subunits bind directly to a sudomain of the C-terminal tail of mGluR7 in a mutually exclusive manner (Nakajima et al. 1999; O'Connor et al. 1999). This binding is calcium-dependent and occurs on the mGluR7 site that is phosphorylated by PKC. Thus CaM binding is prevented by PKC phosphorylation and conversely, phosphorylation of the receptor is inhibited by CaM binding (Nakajima et al. 1999). In addition, CaM binding promotes dissociation of Gßy from the receptor making Gßy available to inhibit voltage-dependent calcium channels (O'Connor et al. 1999) and resulting in the inibition of glutamate release from the terminal.
The C-terminal tail of ß2-Adrenergic receptors (ß2-ARs) are directly bound by the Na+/H+ exchanger regulatory factor (NHERF), a protein that regulates the activity of the Na+/H+ exchanger type 3 (NHE3) and subsequently regulates cellular pH (Hall et al. 1998 b) (Fig. 7.1c). While NHERF does not directly regulate ß2-ARs per se, it does directly link these receptors to the G protein-independent modulation (inhibition) of NHE3. Binding of NHERF to ß2-ARs and NHE3 is agonist-dependent but is independent of receptor-mediated activation of adenylyl cyclase. NHERF contains two PDZ domains, the first of which is required for binding to the amino acid motif D-S/T-x-L located at the C-terminal tail of ß2-ARs. This amino acid binding motif is well conserved in other GPCRs and ion channels, and NHERF was subsequently shown to bind to the purinergic P2Y1 receptor (D-T-S-L) and the cystic fibrosis transmembrane conductance regulator (D-T-R-L) as well (Hall et al. 1998a). NHERF also associates and is constitutively phosphorylated by GRK6A on Ser289, but does not associate with GRK6B or GRK6C, alternatively spliced variants that differ from GRK6A at their extreme C termini (Hall et al. 1999 b).
Phototransduction is the fastest known GPCR cascade taking just tens of milliseconds to go from light activation of rhodopsin to the generation of a receptor potential, and less than 100 ms to shut off after the stimulus is terminated (Ranganathan and Stevens 1995). In the Drosophila photoreceptor system, the inaD gene encodes a five PDZ domain protein that assembles different components of the phototransduction system including the transient receptor potential channel (TRP), eye-protein kinase C (eye-PKC), and phospholipase C-ß (PLC-ß). Null inaD mutations that occur in the PDZ domains of InaD result in a dramatic reorganization of signalling molecules and a total loss of transduction complexes (Tsunoda et al. 1997), suggesting that InaD is essential for coordination of the components involved in the activation (PLC-ß and TRP) and the deactivation (eye-PKC) of phototransduction.
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