Figure 1.

Interaction of mGluR5 with scaffolding proteins and signaling molecules. The SH3-multiple ankyrin domain-containing protein (Shank) is a prototypical PDZ scaffolding protein. The PDZ domain of Shank interacts with the c terminus of guanylate kinase-associated protein (GKAP), which is in turn associated with the ionotropic glutamatergic N-methyl-D-aspartate (NMDA) receptor-PSD95 complex. The proline rich domain of Shank interacts with the EVH domain of Homer proteins. Homer proteins form multimers through interactions of their coiled-coil domain and link Shank to mGluR5 and inositol triphosphate (IP₃) or ryanodine receptors. Homer interactions with mGluR5 are further regulated by Preso1 scaffolding proteins. mGluR5 activation by glutamate initiates G_q protein signaling that regulates the function of phospholipase C (PLC). Activation of PLC results in the hydrolysis of phosphatidylinositol-4,5-bisphosphate (PIP₂) to release the second messengers 1,2-Diacylglycerol (DAG) and IP₃. DAG is the physiological activator of protein kinase C (PKC), which in turn activates various intracellular signaling cascades. IP₃ binds to intracellular IP₃ receptors (IP₃R) on the endoplasmic reticulum (ER) membrane initiating Ca²⁺ release from the ER lumen into the cytoplasm, generating complex Ca²⁺ concentration-dependent signals, including temporal oscillations, and propagating waves.