Members of the KCTD family are major regulators of cAMP signaling

Muntean, Brian S.; Marwari, Subhi; Li, Xiaona; Sloan, Douglas C.; Young, Brian; Wohlschlegel, James A.; Martemyanov, Kirill A.

doi:10.1073/pnas.2119237119

Cited by 23 publications

(35 citation statements)

References 69 publications

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“…One simple model is that KCTD12 sequesters Gβγ subcomplexes produced under agonist-induced conditions, thus depleting G protein heterotrimers available for reactivation after prolonged agonist exposure ( Figure 6B ). While other possibilities cannot be presently excluded, and we note recent evidence for an additional effect of KCTD12 on adenylyl cyclase activity, 38 this simple model is attractive because it is sufficient to explain KCTD12 affecting both cAMP and GIRK signaling, as well as enhancing desensitization without changing the acute agonist response. Given that EYA4 and KCTD12 interact with the dissociated G protein subunits rather than with the receptor itself, we conclude (1) that they might regulate G protein signaling beyond MOR and (2) that GPCR-APEX has the sensitivity to monitor a proximal interaction network beyond its direct and indirect interactor partners.…”

Section: Discussionmentioning

confidence: 88%

Profiling the proximal proteome of the mu opioid receptor identifies novel regulators of receptor signaling and trafficking

Polacco

Lobingier

Blythe

et al. 2022

Preprint

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G protein-coupled receptors (GPCRs) regulate many aspects of physiology and represent actionable targets for drug discovery. These receptors translate ligand-dependent input into a cellular response by remodeling protein interaction networks that are exquisitely organized both spatially and temporally. APEX-based proximity biotin labeling combined with quantitative mass spectrometry has emerged as a powerful approach for capturing all aspects of this dynamic ligand-dependent cellular re-organization. However, a major challenge in this approach is the extraction of salient information from these highly complex datasets. Here, we describe a computational framework for analyzing proximity labeling datasets that reliably predicts the subcellular location of GPCRs and deconvolutes spatial and temporal components of protein interaction network organization. Focusing on the mu-opioid receptor and its activation with distinct agonist drugs, we demonstrate the applicability of this framework to resolve agonist-specific differences in receptor localization and trafficking as well as the protein interaction networks it engages. Using this approach, we discover two novel protein network components which produce widespread, yet distinct, effects on G protein-dependent signaling. While the framework is broadly applicable to proximity biotin labeling datasets, it holds specific promise for further rationalizing GPCR drug discovery efforts by providing an unbiased assessment of ligand-dependent effects, and by enabling the discovery of additional network components for consideration as novel therapeutic targets.

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Section: Discussionmentioning

confidence: 88%

Profiling the proximal proteome of the mu opioid receptor identifies novel regulators of receptor signaling and trafficking

Polacco

Lobingier

Blythe

et al. 2022

Preprint

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“…In previous work, we examined the opposite hypothesis. We demonstrated that GPCR stimulation of cAMP generation was significantly augmented during loss of KCTD (2, 5, or 17) in primary striatal neurons, an effect attributed to increased level of Gβγ ( 25 ). Here, we found the corollary effect of KCTD overexpression in primary striatal neurons: KCTDs that interact with Gβγ significantly reduced stimulatory dopamine receptor signaling to cAMP.…”

Section: Discussionmentioning

confidence: 96%

“…We utilized the cAMP pathway to examine how principles that guide KCTD–Gβγ interaction impact signal transmission in live cells. This was a rational starting point given significant alterations in cAMP signaling have been linked to KCTD knockout ( 24 , 25 ) whereas KCTD overexpression influence downstream to cAMP has not yet been reported. Future studies in additional Gβγ-dependent signaling modalities, such as K + flux through GIRK channels, will be of great interest.…”

Section: Discussionmentioning

confidence: 99%

“…Curiously, the best characterized substrate for ubiquitination is Gβγ ( 23 ), which is mediated through interaction with KCTD2 and KCTD5 ( 24 ). Indeed, loss of KCTD2 and KCTD5 (as well as KCTD17) leads to enhanced Gβγ-dependent second messenger signaling downstream through the cAMP pathway ( 25 ). Despite substantial functional information resulting from interactions between Gβγ with a few KCTDs ( 12 ), the molecular determinants underpinning such interaction are still unclear.…”

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confidence: 99%

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Multiple potassium channel tetramerization domain (KCTD) family members interact with Gβγ, with effects on cAMP signaling

Sloan¹,

Cryan²,

Muntean³

2023

Journal of Biological Chemistry

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“…For example, KCTD17 (Carpenter) and other KCTD family members regulate cAMP signaling 51 and are implicated in neurological disorders 52 . As well, CARTPT (Carpenter, Walker) is a prepropeptide related to the addiction gene CART (Cocaine and Amphetamine Regulated Transcript) 53,54 .…”

Section: Discussionmentioning

confidence: 99%

An approach for prioritizing candidate genes from RNA-seq using preclinical cocaine self-administration datasets as a test case

Vannan

Dell’Orco²,

Perrone‐Bizzozero³

et al. 2023

Preprint

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RNA-sequencing (RNA-seq) technology has led to a surge of neuroscience research using animal models to probe the complex molecular mechanisms underlying brain function and behavior, including substance use disorders (SUDs). However, findings from rodent studies often fail to be translated into clinical treatments. Here, we developed a novel pipeline for narrowing candidate genes from preclinical studies by translational potential and demonstrated utility of this model in three RNA-seq studies of rodent self-administration. This pipeline uses evolutionary conservation and preferential expression of genes across brain tissues to prioritize candidate genes, increasing the translational utility of RNA-seq in model organisms. We found only 1 differentially-expressed gene (DEG) in any dataset after correcting for multiple testing (FDR < 0.05 or < 0.1), raising concerns about false positives and low statistical power that may impact these and other RNA-seq datasets. Thus, we demonstrate the utility of our prioritization pipeline using an uncorrected p-value. Curiously, even with an uncorrected p-value of 0.05 we saw low overlap of DEGs across the 3 selected datasets. Thus, we also advocate for improved RNA-seq data collection, statistical testing, and metadata reporting that will bolster the field’s ability to identify reliable candidate genes and compare results across studies.

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Members of the KCTD family are major regulators of cAMP signaling

Cited by 23 publications

References 69 publications

Profiling the proximal proteome of the mu opioid receptor identifies novel regulators of receptor signaling and trafficking

Profiling the proximal proteome of the mu opioid receptor identifies novel regulators of receptor signaling and trafficking

Multiple potassium channel tetramerization domain (KCTD) family members interact with Gβγ, with effects on cAMP signaling

An approach for prioritizing candidate genes from RNA-seq using preclinical cocaine self-administration datasets as a test case

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