Role of G Protein-Coupled Receptors in the Regulation of Structural Plasticity and Cognitive Function

We review how motile cells regulate actin filament assembly at their leading edge. Activation of cell surface receptors generates signals (including activated Rho family GTPases) that converge on integrating proteins of the WASp family (WASp, N-WASP, and Scar/WAVE). WASP family proteins stimulate Arp2/3 complex to nucleate actin filaments, which grow at a fixed 70 degrees angle from the side of pre-existing actin filaments. These filaments push the membrane forward as they grow at their barbed ends. Arp2/3 complex is incorporated into the network, and new filaments are capped rapidly, so that activated Arp2/3 complex must be supplied continuously to keep the network growing. Hydrolysis of ATP bound to polymerized actin followed by phosphate dissociation marks older filaments for depolymerization by ADF/cofilins. Profilin catalyzes exchange of ADP for ATP, recycling actin back to a pool of unpolymerized monomers bound to profilin and thymosin-beta 4 that is poised for rapid elongation of new barbed ends.

Recent studies show that dendritic spines are dynamic structures. Their rapid creation, destruction and shape-changing are essential for short- and long-term plasticity at excitatory synapses on pyramidal neurons in the cerebral cortex. The onset of long-term potentiation, spine-volume growth and an increase in receptor trafficking are coincident, enabling a 'functional readout' of spine structure that links the age, size, strength and lifetime of a synapse. Spine dynamics are also implicated in long-term memory and cognition: intrinsic fluctuations in volume can explain synapse maintenance over long periods, and rapid, activity-triggered plasticity can relate directly to cognitive processes. Thus, spine dynamics are cellular phenomena with important implications for cognition and memory. Furthermore, impaired spine dynamics can cause psychiatric and neurodevelopmental disorders. Copyright 2010 Elsevier Ltd. All rights reserved.

Opioid receptors have been targeted for the treatment of pain and related disorders for thousands of years and remain the most widely used analgesics in the clinic. Mu (μ), kappa (κ), and delta (δ) opioid receptors represent the originally classified receptor subtypes, with opioid receptor like-1 (ORL1) being the least characterized. All four receptors are G-protein coupled and activate inhibitory G proteins. These receptors form homo- and heterodimeric complexes and signal to kinase cascades and scaffold a variety of proteins.The authors discuss classic mechanisms and developments in understanding opioid tolerance and opioid receptor signaling and highlight advances in opioid molecular pharmacology, behavioral pharmacology, and human genetics. The authors put into context how opioid receptor signaling leads to the modulation of behavior with the potential for therapeutic intervention. Finally, the authors conclude there is a continued need for more translational work on opioid receptors in vivo.