[3] PDZ domains also play a highly significant role in the anchoring of cell surface receptors (such as Cftr and FZD7) to the actin cytoskeleton via mediators like NHERF and ezrin.

In September 1995, Dr. Mary B. Kennedy of the California Institute of Technology wrote a letter of correction to Trends in Biomedical Sciences.

[3] A commonly accepted theory for the binding pocket of the PDZ domain is that it is constituted by several hydrophobic amino acids, apart from the GLGF sequence mentioned earlier, the mainchain atoms of which form a nest (protein structural motif) binding the C-terminal carboxylate of the protein or peptide ligand.

[14] PDZ domains play a vital role in organizing and maintaining complex scaffolding formations.

[13] In the neuron, making sense of neurotransmitter activity requires specific receptors to be located in the lipid membrane at the synapse.

In the human brain, nitric oxide often acts in the synapse to modify cGMP levels in response to NMDA receptor activation.

[16] With nNOS located closely to NMDA receptors, it will be activated immediately after calcium ions begin entering the cell.

This regulation is usually a result of the co-localization of multiple signaling molecules such as in the example with nNos and NMDA receptors.

The signaling pathway of the human protein tyrosine phosphatase non-receptor type 4 (PTPN4) is regulated by PDZ domains.

Binding the PDZ domain of this phosphatase results in a loss of enzyme activity, which leads to apoptosis.

[18] PDZ domains also have a regulatory role in mechanosensory signaling in proprioceptors and vestibular and auditory hair cells.

The protein Whirlin (WHRN) localizes in the post-synaptic neurons of hair cells that transform mechanical movement into action potentials that the body can interpret.

When the one of these PDZ domains is inhibited, the signaling pathways of the neurons are disrupted, resulting in auditory, visual, and vestibular impairment.

Scientists have demonstrated that when the Ser-411 residue of the β2-AR PDZ binding domain, which interacts directly with EBP50, is phosphorylated, the receptor is degraded.

[20] The role played by PDZ domains and their binding sites indicate a regulative relevance beyond simply receptor protein localization.

In some examples, phosphorylation of amino acid side chains eliminates the ability of the PDZ domain to form hydrogen bonds, disrupting the normal binding patterns.

[23] Another way phosphorylation can disrupt regular PDZ domain function is by altering the charge ratio and further affecting binding and signaling.

These studies show that allosteric effects of certain proteins can affect the binding affinity for different substrates.

The first two PDZ domains of PSD-95 bind to the C-terminus of NMDA receptors and anchor them in the membrane at the point of neurotransmitter release.

The third and final PDZ domain links to cysteine-rich PDZ-binding protein (CRIPT), which allows PSD-95 to associate with the cytoskeleton.

[14] This interaction is vital for proper localization of AMPA receptors, which play a large part in memory storage.

Instead of mediating receptors near ion channels, as is the case with GRIP and PSD-95, HOMER is involved in metabotropic glutamate signaling.

HOMER expression is measured at high levels during embryologic stages in rats, suggesting an important developmental function.