PRRT2 Modulates Presynaptic Ca Influx by Interacting with P/Q-type Channels

Overview

Journal Cell Rep

Publisher Cell Press

Specialties Biology
Cell Biology
Molecular Biology

Date 2021 Jun 16

PMID 34133925

Citations 8

Authors

Daniele Ferrante

Bruno Sterlini

Cosimo Prestigio

Antonella Marte

Anna Corradi

Franco Onofri

Giorgio Tortarolo

Giuseppe Vicidomini

Andrea Petretto

Jessica Muia

Agnes Thalhammer

Pierluigi Valente

Lorenzo A Cingolani

Fabio Benfenati

Pietro Baldelli

Affiliations

Soon will be listed here.

Abstract

Loss-of-function mutations in proline-rich transmembrane protein-2 (PRRT2) cause paroxysmal disorders associated with defective Ca dependence of glutamatergic transmission. We find that either acute or constitutive PRRT2 deletion induces a significant decrease in the amplitude of evoked excitatory postsynaptic currents (eEPSCs) that is insensitive to extracellular Ca and associated with a reduced contribution of P/Q-type Ca channels to the EPSC amplitude. This synaptic phenotype parallels a decrease in somatic P/Q-type Ca currents due to a decreased membrane targeting of the channel with unchanged total expression levels. Co-immunoprecipitation, pull-down assays, and proteomics reveal a specific and direct interaction of PRRT2 with P/Q-type Ca channels. At presynaptic terminals lacking PRRT2, P/Q-type Ca channels reduce their clustering at the active zone, with a corresponding decrease in the P/Q-dependent presynaptic Ca signal. The data highlight the central role of PRRT2 in ensuring the physiological Ca sensitivity of the release machinery at glutamatergic synapses.

Citing Articles

Paroxysmal Kinesigenic Dyskinesia: Genetics and Pathophysiological Mechanisms.

Xu J, Li H, Wu Z Neurosci Bull. 2023; 40(7):952-962.

PMID: 38091244 PMC: 11250761. DOI: 10.1007/s12264-023-01157-z.

Translating Genetic Discovery into a Mechanistic Understanding of Pediatric Movement Disorders: Lessons from Genetic Dystonias and Related Disorders.

Lin W Adv Genet (Hoboken). 2023; 4(2):2200018.

PMID: 37288166 PMC: 10242408. DOI: 10.1002/ggn2.202200018.

Pain-causing stinging nettle toxins target TMEM233 to modulate Na1.7 function.

Jami S, Deuis J, Klasfauseweh T, Cheng X, Kurdyukov S, Chung F Nat Commun. 2023; 14(1):2442.

PMID: 37117223 PMC: 10147923. DOI: 10.1038/s41467-023-37963-2.

Rescue of neuropsychiatric phenotypes in a mouse model of 16p11.2 duplication syndrome by genetic correction of an epilepsy network hub.

Forrest M, Dos Santos M, Piguel N, Wang Y, Hawkins N, Bagchi V Nat Commun. 2023; 14(1):825.

PMID: 36808153 PMC: 9938216. DOI: 10.1038/s41467-023-36087-x.

A Push-Pull Mechanism Between PRRT2 and β4-subunit Differentially Regulates Membrane Exposure and Biophysical Properties of NaV1.2 Sodium Channels.

Valente P, Marte A, Franchi F, Sterlini B, Casagrande S, Corradi A Mol Neurobiol. 2022; 60(3):1281-1296.

PMID: 36441479 PMC: 9899197. DOI: 10.1007/s12035-022-03112-x.

References

Faraone S, Perlis R, Doyle A, Smoller J, Goralnick J, Holmgren M . Molecular genetics of attention-deficit/hyperactivity disorder. Biol Psychiatry. 2005; 57(11):1313-23. DOI: 10.1016/j.biopsych.2004.11.024. View

Pozzi D, Lignani G, Ferrea E, Contestabile A, Paonessa F, DAlessandro R . REST/NRSF-mediated intrinsic homeostasis protects neuronal networks from hyperexcitability. EMBO J. 2013; 32(22):2994-3007. PMC: 3831314. DOI: 10.1038/emboj.2013.231. View

Heron S, Dibbens L . Role of PRRT2 in common paroxysmal neurological disorders: a gene with remarkable pleiotropy. J Med Genet. 2013; 50(3):133-9. DOI: 10.1136/jmedgenet-2012-101406. View

Shen Y, Ge W, Li Y, Hirano A, Lee H, Rohlmann A . Protein mutated in paroxysmal dyskinesia interacts with the active zone protein RIM and suppresses synaptic vesicle exocytosis. Proc Natl Acad Sci U S A. 2015; 112(10):2935-41. PMC: 4364199. DOI: 10.1073/pnas.1501364112. View

Valtorta F, Benfenati F, Zara F, Meldolesi J . PRRT2: from Paroxysmal Disorders to Regulation of Synaptic Function. Trends Neurosci. 2016; 39(10):668-679. DOI: 10.1016/j.tins.2016.08.005. View

Wright P, Dyson H . Intrinsically disordered proteins in cellular signalling and regulation. Nat Rev Mol Cell Biol. 2014; 16(1):18-29. PMC: 4405151. DOI: 10.1038/nrm3920. View

Thalhammer A, Contestabile A, Ermolyuk Y, Ng T, Volynski K, Soong T . Alternative Splicing of P/Q-Type Ca Channels Shapes Presynaptic Plasticity. Cell Rep. 2017; 20(2):333-343. DOI: 10.1016/j.celrep.2017.06.055. View

Lerche H . Synaptic or ion channel modifier? PRRT2 is a chameleon-like regulator of neuronal excitability. Brain. 2018; 141(4):938-941. DOI: 10.1093/brain/awy073. View

Lee H, Huang Y, Bruneau N, Roll P, Roberson E, Hermann M . Mutations in the gene PRRT2 cause paroxysmal kinesigenic dyskinesia with infantile convulsions. Cell Rep. 2012; 1(1):2-12. PMC: 3334308. DOI: 10.1016/j.celrep.2011.11.001. View

10.

Rossi P, Sterlini B, Castroflorio E, Marte A, Onofri F, Valtorta F . A Novel Topology of Proline-rich Transmembrane Protein 2 (PRRT2): HINTS FOR AN INTRACELLULAR FUNCTION AT THE SYNAPSE. J Biol Chem. 2016; 291(12):6111-23. PMC: 4813553. DOI: 10.1074/jbc.M115.683888. View

11.

Michetti C, Castroflorio E, Marchionni I, Forte N, Sterlini B, Binda F . The PRRT2 knockout mouse recapitulates the neurological diseases associated with PRRT2 mutations. Neurobiol Dis. 2016; 99:66-83. PMC: 5321265. DOI: 10.1016/j.nbd.2016.12.018. View

12.

Coleman J, Jouannot O, Ramakrishnan S, Zanetti M, Wang J, Salpietro V . PRRT2 Regulates Synaptic Fusion by Directly Modulating SNARE Complex Assembly. Cell Rep. 2018; 22(3):820-831. PMC: 5792450. DOI: 10.1016/j.celrep.2017.12.056. View

13.

Sterlini B, Romei A, Parodi C, Aprile D, Oneto M, Aperia A . An interaction between PRRT2 and Na/K ATPase contributes to the control of neuronal excitability. Cell Death Dis. 2021; 12(4):292. PMC: 7969623. DOI: 10.1038/s41419-021-03569-z. View

14.

Tamamaki N, Yanagawa Y, Tomioka R, Miyazaki J, Obata K, Kaneko T . Green fluorescent protein expression and colocalization with calretinin, parvalbumin, and somatostatin in the GAD67-GFP knock-in mouse. J Comp Neurol. 2003; 467(1):60-79. DOI: 10.1002/cne.10905. View

15.

Valente P, Lignani G, Medrihan L, Bosco F, Contestabile A, Lippiello P . Cell adhesion molecule L1 contributes to neuronal excitability regulating the function of voltage-gated Na+ channels. J Cell Sci. 2016; 129(9):1878-91. DOI: 10.1242/jcs.182089. View

16.

Ebrahimi-Fakhari D, Saffari A, Westenberger A, Klein C . The evolving spectrum of PRRT2-associated paroxysmal diseases. Brain. 2015; 138(Pt 12):3476-95. DOI: 10.1093/brain/awv317. View

17.

Fruscione F, Valente P, Sterlini B, Romei A, Baldassari S, Fadda M . PRRT2 controls neuronal excitability by negatively modulating Na+ channel 1.2/1.6 activity. Brain. 2018; 141(4):1000-1016. PMC: 5888929. DOI: 10.1093/brain/awy051. View

18.

Barr C, Feng Y, Wigg K, Bloom S, Roberts W, Malone M . Identification of DNA variants in the SNAP-25 gene and linkage study of these polymorphisms and attention-deficit hyperactivity disorder. Mol Psychiatry. 2000; 5(4):405-9. DOI: 10.1038/sj.mp.4000733. View

19.

Corradini I, Donzelli A, Antonucci F, Welzl H, Loos M, Martucci R . Epileptiform activity and cognitive deficits in SNAP-25(+/-) mice are normalized by antiepileptic drugs. Cereb Cortex. 2012; 24(2):364-76. DOI: 10.1093/cercor/bhs316. View

20.

Mill J, Richards S, Knight J, Curran S, Taylor E, Asherson P . Haplotype analysis of SNAP-25 suggests a role in the aetiology of ADHD. Mol Psychiatry. 2004; 9(8):801-10. DOI: 10.1038/sj.mp.4001482. View