Intracellular GPCRs Play Key Roles in Synaptic Plasticity

Abstract

The trillions of synaptic connections within the human brain are shaped by experience and neuronal activity both of which underlie synaptic plasticity and ultimately learning and memory. G protein-coupled receptors (GPCRs) play key roles in synaptic plasticity by strengthening or weakening synapses and/or shaping dendritic spines. While most studies of synaptic plasticity have focused on cell surface receptors and their downstream signaling partners, emerging data point to a critical new role for the very same receptors to signal from inside the cell. Intracellular receptors have been localized to nuclear, endoplasmic reticulum, lysosomes and mitochondria. From these intracellular positions, such receptors may couple to different signaling systems, display unique desensitization patterns and/or show distinct patterns of subcellular distribution. Intracellular GPCRs can be activated at the cell surface, endocytosed and transported to an intracellular site or simply activated in situ by de novo ligand synthesis, diffusion of permeable ligands or active transport of nonpermeable ligands. Current findings reinforce the notion that intracellular GPCRs play a dynamic role in synaptic plasticity and learning and memory. As new intracellular GPCR roles are defined, the need to selectively tailor agonists and/or antagonists to both intracellular and cell surface receptors may lead to the development of more effective therapeutic tools.

mGlu1 tonically regulates levels of calcium‐permeable AMPA receptors in cultured nucleus accumbens neurons through retinoic acid signaling and protein translation

“…Resolving the relationship between localization and function of mGlu1 versus mGlu5 is an important challenge for future studies. A complicating factor is the existence of a substantial intracellular pool of these receptors in the adult rat NAc (Mitrano & Smith, ) combined with evidence that mGlu5 and other GPCRs can signal from intracellular compartments (Jong, Harmon, & O'Malley, ). Furthermore, group I mGluRs are expressed by astrocytes (Hovelsø et al., ) and we cannot exclude a role for this mGluR population in our observed effects.…”

Regulation of bifunctional proteins in cells: Lessons from the phospholipase Cβ/G protein pathway

“…GPCRs are a large family of seven transmembrane proteins that interact and respond to a diverse array of ligands that include hormones, neurotransmitters, vasodilators, many pharmaceutical agents, and light. Ligand binding allows GPCRs to activate their associated G proteins by catalyzing the exchange of GDP for GTP on the Gα subunits peripherally bound to the plasma membrane . Heterotrimeric G proteins are composed of three subunits (α, β, and γ).…”

Reaction of cell membrane bilayers “as a variable capacitor” with G-protein: a reason for neurotransmitter signaling

“…These effects allow one for introducing a capacitive susceptibility that can be resonates with self-induction effect of helical coils in G proteins. Table 5 indicates the calculated helical proteins self-induction (of some G-proteins component) [63][64][65][66][67][68][69][70][71][72][73][74] through resonance with capacitances of several phospholipids membranes. Due to the greater inductance compared to conductance in coils, the helical coils of DNA, mRNA, and trance membrane proteins can be resonate with a capacitive susceptibility of phospholipids capacitors in biological phenomenon.…”