Gαo is a major determinant of cAMP signaling in the pathophysiology of movement disorders

Muntean, Brian S.; Masuho, Ikuo; Dao, Maria; Sutton, Laurie P.; Zucca, Stefano; Iwamoto, Hideki; Patil, Dipak N.; Wang, Dandan; Birnbaumer, Lutz; Blakely, Randy D.; Grill, Brock; Martemyanov, Kirill A.

doi:10.1016/j.celrep.2021.108718

Cited by 61 publications

(104 citation statements)

References 102 publications

(126 reference statements)

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“…To assess behavioral implications of KCTD5 reduction, we employed a panel of assays for motor behaviors sensitive to perturbations in the striatal circuitry ( 34 ). We found that Kctd5 +/− mice showed significant hindlimb-clasping phenotype, a hallmark dystonic feature absent in wild-type ( Kctd5 +/+ ) ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…In alignment with our behavioral observation, clinical variants in the Zip14-encoding gene, Slc39a14, have recently been implicated in parkinsonism–dystonia ( 61 ). This connects KCTDs and Zip14 to a series of striatal cAMP regulators causal to movement disorders that includes AC5 ( 62 ), Gαolf ( 63 ), Gαo ( 34 , 64 , 65 ), Gβ1 ( 66 , 67 ), and PDE10A ( 68 ). The diversity of KCTD interactome, defined in part by their cooperative hetero-oligomeric complex assembly, introduces a distinct signaling paradigm to our understanding of cAMP regulation.…”

Section: Discussionmentioning

confidence: 99%

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Members of the KCTD family are major regulators of cAMP signaling

Muntean

Marwari

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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Cyclic adenosine monophosphate (cAMP) is a pivotal second messenger with an essential role in neuronal function. cAMP synthesis by adenylyl cyclases (AC) is controlled by G protein–coupled receptor (GPCR) signaling systems. However, the network of molecular players involved in the process is incompletely defined. Here, we used CRISPR/Cas9–based screening to identify that members of the potassium channel tetradimerization domain (KCTD) family are major regulators of cAMP signaling. Focusing on striatal neurons, we show that the dominant isoform KCTD5 exerts its effects through an unusual mechanism that modulates the influx of Zn2+ via the Zip14 transporter to exert unique allosteric effects on AC. We further show that KCTD5 controls the amplitude and sensitivity of stimulatory GPCR inputs to cAMP production by Gβγ-mediated AC regulation. Finally, we report that KCTD5 haploinsufficiency in mice leads to motor deficits that can be reversed by chelating Zn2+. Together, our findings uncover KCTD proteins as major regulators of neuronal cAMP signaling via diverse mechanisms.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Members of the KCTD family are major regulators of cAMP signaling

Muntean

Marwari

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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“…Despite some insights [14,21], the molecular mechanisms of the Gαo/Gαi1 mutants driving the pediatric encephalopathies still remain unclear. A basic feature of a G protein is its ability to bind and hydrolyze GTP.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, all point mutations (>30) within the coding region of GNAO1 correspond to highly conserved residues (e.g., identical between human, fruit fly and worm), indicating their involvement in basic Gαo functions [20]. Despite some insights into the potential mechanisms of pathological mutations [14,21], the molecular mechanisms of Gαo mutants driving to abnormal movement disorders and epilepsy still await the much-needed clarification to reveal potential therapeutic targeting approaches.…”

Section: Introductionmentioning

confidence: 99%

Pediatric Encephalopathy: Clinical, Biochemical and Cellular Insights into the Role of Gln52 of GNAO1 and GNAI1 for the Dominant Disease

Solis

Кожанова

Koval

et al. 2021

Cells

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Heterotrimeric G proteins are immediate transducers of G protein-coupled receptors—the biggest receptor family in metazoans—and play innumerate functions in health and disease. A set of de novo point mutations in GNAO1 and GNAI1, the genes encoding the α-subunits (Gαo and Gαi1, respectively) of the heterotrimeric G proteins, have been described to cause pediatric encephalopathies represented by epileptic seizures, movement disorders, developmental delay, intellectual disability, and signs of neurodegeneration. Among such mutations, the Gln52Pro substitutions have been previously identified in GNAO1 and GNAI1. Here, we describe the case of an infant with another mutation in the same site, Gln52Arg. The patient manifested epileptic and movement disorders and a developmental delay, at the onset of 1.5 weeks after birth. We have analyzed biochemical and cellular properties of the three types of dominant pathogenic mutants in the Gln52 position described so far: Gαo[Gln52Pro], Gαi1[Gln52Pro], and the novel Gαo[Gln52Arg]. At the biochemical level, the three mutant proteins are deficient in binding and hydrolyzing GTP, which is the fundamental function of the healthy G proteins. At the cellular level, the mutants are defective in the interaction with partner proteins recognizing either the GDP-loaded or the GTP-loaded forms of Gαo. Further, of the two intracellular sites of Gαo localization, plasma membrane and Golgi, the former is strongly reduced for the mutant proteins. We conclude that the point mutations at Gln52 inactivate the Gαo and Gαi1 proteins leading to aberrant intracellular localization and partner protein interactions. These features likely lie at the core of the molecular etiology of pediatric encephalopathies associated with the codon 52 mutations in GNAO1/GNAI1.

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“…The number of discovered different -mostly missense point -mutations in GNAO1 causing this malady steadily increases every year since the rst 2013' report 4 . However, despite some insights 4,19,46 , the understanding of the molecular etiology underlying the pathological developments has been largely missing. This delay in the understanding blocks development of therapies to treat the patients.…”

Section: Discussionmentioning

confidence: 99%

Restoration of the GTPase activity of Gαo mutants by Zn2+ in GNAO1 encephalopathy models

Larasati¹,

Savitsky²,

Koval³

et al. 2021

Preprint

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GNAO1 encephalopathy is a rare pediatric disease characterized by motor dysfunction, developmental delay, and epileptic seizures1-3. De novo point mutations in the gene encoding Gαo, the major neuronal G protein, lie at the core of this dominant genetic malady4. Half of the clinical case mutations fall on codons Gly203, Arg209, or Glu246 near the GTP binding/hydrolysis pocket of Gαo1-3. We here show that these pathologic mutations strongly speed up GTP uptake and inactivate GTP hydrolysis by Gαo, resulting in constitutive GTP binding by the G protein. Molecular dynamics simulations indicate that the mutations cause displacement of Gln205, the key to GTP hydrolysis. Decreased interactions with cellular partners including RGS19 suggest that despite the enhanced GTP residence, the mutants fail to fully adopt the activated conformation and thus transmit the signal. Through a high-throughput screening of approved drugs aiming at correction of this core biochemical dysfunction, we identify zinc pyrithione and Zn2+ ions as agents restoring the active conformation, GTPase activity, and cellular interactions of the encephalopathy mutants, with a negligible effect on wild type Gαo. We describe a Drosophila model of GNAO1 encephalopathy and show that dietary zinc supplementation restores the motor function and longevity of the mutant flies. With zinc supplements frequently recommended for diverse human neurological conditions, our work spanning from identification of the core biochemical defect in Gαo mutants and cellular interactions analysis to high-throughput screening and animal validation of the deficiency-correcting drug defines the potential therapy for GNAO1 encephalopathy patients.

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Gαo is a major determinant of cAMP signaling in the pathophysiology of movement disorders

Cited by 61 publications

References 102 publications

Members of the KCTD family are major regulators of cAMP signaling

Members of the KCTD family are major regulators of cAMP signaling

Pediatric Encephalopathy: Clinical, Biochemical and Cellular Insights into the Role of Gln52 of GNAO1 and GNAI1 for the Dominant Disease

Restoration of the GTPase activity of Gαo mutants by Zn2+ in GNAO1 encephalopathy models

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