G protein-coupled receptors and the regulation of autophagy

Abstract

Autophagy is an important catabolic cellular process that eliminates damaged and unnecessary cytoplasmic proteins and organelles. Basal autophagy occurs during normal physiological conditions, but the activity of this process can be significantly altered in human diseases. Thus, defining the regulatory inputs and signals that control autophagy is essential. Nutrients are key modulators of autophagy. While autophagy is generally accepted to be regulated in a cell autonomous fashion, recent studies suggest nutrients can modulate autophagy in a systemic manner by inducing the secretion of hormones and neurotransmitters that regulate G protein-coupled receptors (GPCRs). Emerging studies show that GPCRs also regulate autophagy by directly detecting extracellular nutrients. We review the role of GPCRs in autophagy regulation, highlighting their potential as therapeutic drug targets.

Focal Adhesion Kinase-mediated Phosphorylation of Beclin1 Protein Suppresses Cardiomyocyte Autophagy and Initiates Hypertrophic Growth

“…Despite mounting evidence for a causal role of autophagy suppression in the promotion of compensatory hypertrophy (4,11,31,(42)(43)(44)(45)(46), the mechanistic links between pressure overload and adrenergic signaling-induced autophagic suppression have remained largely unsolved. A prior report indicated that endothelin-1 can suppress autophagy by inducing ubiquitination and degradation of Atg14L through ZBTB16-Cullin3-Rock1 E3 ubiquitin ligase complex (47).…”

Organelle-Specific Initiation of Autophagy

“…These include (but are not limited to): (1) free fatty acid receptor 1 (FFAR1), FFAR2, FFAR3, and FFAR4, which are activated by free fatty acids; (2) glucagon receptor (GCGR), which responds to glucagon; (3) cholinergic receptor, muscarinic 3 (CHRM3), which is activated by acetylcholine; (4) adrenoceptor beta 2, surface (ADRB2), which is engaged by norepinephrine; and (5) purinergic receptor P2Y, G protein-coupled, 13 (P2RY13), which is responsive to ADP (Wauson et al, 2014). The signal transduction pathways that relay the liganddependent activation of these receptors to the autophagic machinery are heterogeneous but generally involve elevations in the intracellular levels of inositol-1,4,5,-triphosphate and diacylglycerol, or cAMP, which de facto stimulate autophagy via the AMPK/MTORC1 hub (Wauson et al, 2014).…”

“…G protein-coupled receptor, class C, group 6, member A (GPRC6A), calcium-sensing receptor (CASR), gamma-aminobutyric acid B receptor 1 (GABBR1), heteromeric taste receptors, and various metabotropic glutamate receptors, all of which are activated by one or several amino acids, share the ability to repress autophagy in the presence of their ligands (Wauson et al, 2014). The molecular cascades connecting these GPCRs to the autophagic machinery are not completely understood but have been proposed to involve G proteins that provoke a decrease in the intracellular levels of cAMP, resulting in the suppression of AMPK activity (Wauson et al, 2014).…”

“…The molecular cascades connecting these GPCRs to the autophagic machinery are not completely understood but have been proposed to involve G proteins that provoke a decrease in the intracellular levels of cAMP, resulting in the suppression of AMPK activity (Wauson et al, 2014). In addition, heteromeric taste receptors have been shown to repress autophagy via a Ca 2+ -dependent mechanism that directly involves amino acid sensing by MTORC1 (Wauson et al, 2012).…”

“…Examples of Non-selective and Targeted Autophagic Responses Initiated at Specific Subcellular CompartmentsChen et al, 2014;Geisler et al, 2010;Okatsu et al, 2015;Narendra et al, 2010;Tanaka et al, 2010 CCFs destined to disposal have signs of ongoing DDR and are tagged with p62Ivanov et al, 2013;Young et al, 2009 Plasma membrane death receptor ligands non-selective stimulate autophagy via JNK1 and components of the NF-kB signaling pathwayCriollo et al, 2010; Criollo et al, 2011;He et al, 2012;Keller et al, 2011 promote autophagy via MYD88 or TICAM1Delgado et al, 2008;Knodler and Celli, 2011;Ma et al, 2013;Shi and Kehrl, 2008 amino acid deprivation non-selective several GPCRs repress autophagy in response to extracellular amino acidsWauson et al, 2012;Wauson et al, 2014Inoki et al, 2002Leto and Saltiel, 2012;Manning and Cantley, 2007;Wang et al, 2012; Wei et al, 2013 Continued …”