GPCR signalling from within the cell

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Abstract

<div class="section"> <a class="named-anchor" id="bph14023-sec-1000">  </a> <p class="first" id="d98198e182">Traditionally, signal transduction from GPCRs is thought to emanate from the cell surface where receptor interactions with external stimuli can be transformed into a broad range of cellular responses. However, emergent data show that numerous GPCRs are also associated with various intracellular membranes where they may couple to different signalling systems, display unique desensitization patterns and/or exhibit distinct patterns of subcellular distribution. Although many GPCRs can be activated at the cell surface and subsequently endocytosed and transported to a unique intracellular site, other intracellular GPCRs can be activated <span style="italic-in-any-context">in situ</span> either <span style="italic-in-any-context">via de novo</span> 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 various biological functions including learning and memory, contractility and angiogenesis. 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. </p> </div><div class="section"> <a class="named-anchor" id="bph14023-sec-1100">  </a> <h5 class="section-title" id="d98198e191">Linked Articles</h5> <p id="d98198e193">This article is part of a themed section on Molecular Pharmacology of GPCRs. To view the other articles in this section visit <a data-untrusted="" href="http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.21/issuetoc" id="d98198e195" target="xrefwindow">http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.21/issuetoc</a> </p> </div>

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Manoj K. Shukla, R Lefkowitz, SeungKirl Ahn … (2011)

The concept of biased agonism has recently come to the fore with the realization that seven-transmembrane receptors (7TMRs, also known as G protein-coupled receptors, or GPCRs) activate complex signaling networks and can adopt multiple active conformations upon agonist binding. As a consequence, the "efficacy" of receptors, which was classically considered linear, is now recognized as pluridimensional. Biased agonists selectively stabilize only a subset of receptor conformations induced by the natural "unbiased" ligand, thus preferentially activating certain signaling mechanisms. Such agonists thus reveal the intriguing possibility that one can direct cellular signaling with unprecedented precision and specificity and support the notion that biased agonists may identify new classes of therapeutic agents that have fewer side effects. This review focuses on one particular class of biased ligands that has the ability to alter the balance between G protein-dependent and β-arrestin-dependent signal transduction.

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A cannabinoid link between mitochondria and memory.

Etienne Hebert-Chatelain, Tifany Desprez, Román Serrat … (2016)

Cellular activity in the brain depends on the high energetic support provided by mitochondria, the cell organelles which use energy sources to generate ATP. Acute cannabinoid intoxication induces amnesia in humans and animals, and the activation of type-1 cannabinoid receptors present at brain mitochondria membranes (mtCB1) can directly alter mitochondrial energetic activity. Although the pathological impact of chronic mitochondrial dysfunctions in the brain is well established, the involvement of acute modulation of mitochondrial activity in high brain functions, including learning and memory, is unknown. Here, we show that acute cannabinoid-induced memory impairment in mice requires activation of hippocampal mtCB1 receptors. Genetic exclusion of CB1 receptors from hippocampal mitochondria prevents cannabinoid-induced reduction of mitochondrial mobility, synaptic transmission and memory formation. mtCB1 receptors signal through intra-mitochondrial Gαi protein activation and consequent inhibition of soluble-adenylyl cyclase (sAC). The resulting inhibition of protein kinase A (PKA)-dependent phosphorylation of specific subunits of the mitochondrial electron transport system eventually leads to decreased cellular respiration. Hippocampal inhibition of sAC activity or manipulation of intra-mitochondrial PKA signalling or phosphorylation of the Complex I subunit NDUFS2 inhibit bioenergetic and amnesic effects of cannabinoids. Thus, the G protein-coupled mtCB1 receptors regulate memory processes via modulation of mitochondrial energy metabolism. By directly linking mitochondrial activity to memory formation, these data reveal that bioenergetic processes are primary acute regulators of cognitive functions.

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Recent progress of cell-penetrating peptides as new carriers for intracellular cargo delivery.

Yu-Fang Jin, Yun Wang, Shengrong Guo … (2014)

The plasma membrane as a selectively permeable barrier of living cells is essential to cell survival and function. In many cases, however, the efficient passage of exogenous bioactive molecules through the plasma membrane remains a major hurdle for intracellular delivery of cargoes. During the last two decades, the potential of peptides for drug delivery into cells has been highlighted by the discovery of numerous cell-penetrating peptides (CPPs). CPPs serving as carriers can successfully intracellular transport cargoes such as siRNA, nucleic acids, proteins, small molecule therapeutic agents, quantum dots and MRI contrast agents. This review mainly introduces recent advances of CPPs as new carriers for the development of cellular imaging, nuclear localization, pH-sensitive and thermally targeted delivery systems. In particular, we highlight the exploiting of the synergistic effects of targeting ligands and CPPs. What's more, the classification and cellular uptake mechanisms of CPPs are briefly discussed as well. Crown Copyright © 2013. Published by Elsevier B.V. All rights reserved.