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TARPs Modulate Receptor-Mediated Paired-Pulse Depression and Recovery from Desensitization.

ABSTRACT: Transmembrane AMPA receptor regulatory proteins (TARPs) are auxiliary AMPA receptor subunits that play a key role in receptor trafficking and in modulating receptor gating. The ability of TARPs to slow both deactivation and desensitization is isoform specific. However, TARP isoform-specific modulation of receptor properties remains uncharacterized. Here, we compare the isoform-specific effects of γ-2, γ-3, γ-4, and γ-8 TARPs on recovery from desensitization and responses to pairs of brief applications of glutamate. All four isoforms were able to reduce receptor-mediated paired-pulse depression and significantly speed recovery from desensitization in an isoform-specific manner. In the presence of TARPs, recovery time courses were observed to contain two components, fast and slow. The proportion of fast and slow components was determined by the TARP isoform. The time constant of recovery was also altered by the duration of glutamate application. When studies with TARP chimeras were performed, TARP extracellular loops were found to play a vital role in TARP modulation of recovery. Thus, isoform-specific differences in TARP modulation of recovery from desensitization influence receptor responses to repeated brief applications of glutamate, and these differences may impact frequency-dependent synaptic signaling in the mammalian central nervous system.SIGNIFICANCE STATEMENT AMPA receptors are major determinants of excitatory synaptic strength. The channel kinetics of AMPA receptors contribute to the kinetics of synaptic transmission. Transmembrane AMPA receptor regulatory proteins (TARPs) auxiliary subunits can modulate the decay kinetics of AMPA receptors. However, whether TARP isoforms specifically modulate receptor recovery is unclear. Here, we investigated the recovery kinetics of AMPA receptors by expressing various TARP isoforms and chimeras. We observed that the TARP isoforms and duration of glutamate application uniquely modulate time constants and the proportion of fast and slow components through a previously unidentified TARP domain. Given the impact of recovery kinetics on receptor responses to repetitive stimulation such as synaptic transmission, this work will be of great interest in the field of excitatory synaptic transmission research.

SUBMITTER: Devi SPS

PROVIDER: S-EPMC7577600 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundPhosphorylative desensitization of G-protein-coupled receptors contributes significantly to post-myocardial infarction (MI) remodeling and heart failure (HF). Here, we determined whether adiponectin receptors (AdipoRs) 1 and 2 (the 7-transmembrane domain-containing receptors mediating adiponectin functions) are phosphorylatively modified and functionally impaired after MI.Methods and resultsPost-MI HF was induced by coronary artery occlusion. Receptor phosphorylation, kinase expression, and adiponectin function were determined via in vivo, ex vivo, and in vitro models. AdipoR1 and AdipoR2 are not phosphorylated in the normal heart. However, AdipoR1 was significantly phosphorylated after MI, peaking at 7 days and remaining significantly phosphorylated thereafter. The extent of post-MI AdipoR1 phosphorylation positively correlated with the expression level of GPCR kinase (GRK) 2, the predominant GRK isoform upregulated in the failing heart. Cardiac-specific GRK2 knockout virtually abolished post-MI AdipoR1 phosphorylation, whereas virus-mediated GRK2 overexpression significantly phosphorylated AdipoR1 and blocked adiponectin metabolic-regulatory/anti-inflammatory signaling. Mass spectrometry identified serine-7, threonine-24, and threonine-53 (residues located in the n-terminal intracellular AdipoR1 region) as the GRK2 phosphorylation sites. Ex vivo experiments demonstrated that adenosine monophosphate-activated protein kinase activation and the anti-tumor necrosis factor-α effect of adiponectin were significantly inhibited in cardiomyocytes isolated from nonischemic area 7 days after MI. In vivo experiments demonstrated that acute adiponectin administration-induced cardiac GLUT4 translocation and endothelial nitric oxide synthase phosphorylation were blunted 7 days after MI. Continuous adiponectin administration beginning 7 days after MI failed to protect the heart from adverse remodeling and HF progression. Finally, cardiac-specific GRK2 knockdown restored the cardioprotective effect of adiponectin.ConclusionAdipoR1 is phosphorylatively modified and desensitized by GRK2 in failing cardiomyocytes, contributing to post-MI remodeling and HF progression.

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TARPs Modulate Receptor-Mediated Paired-Pulse Depression and Recovery from Desensitization.

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