Distinct Regulation of Beta2 and Beta3 Subunit-containing Cerebellar Synaptic GABAA Receptors by Calcium/calmodulin-dependent Protein Kinase II

Overview

Journal J Neurosci

Specialty Neurology

Date 2008 Jul 25

PMID 18650335

Citations 33

Authors

Catriona M Houston

Alastair M Hosie

Trevor G Smart

Affiliations

Soon will be listed here.

Abstract

Modulation of GABA(A) receptor function and inhibitory synaptic transmission by phosphorylation has profound consequences for the control of synaptic plasticity and network excitability. We have established that activating alpha-calcium/calmodulin-dependent protein kinase II (alpha-CaMK-II) in cerebellar granule neurons differentially affects populations of IPSCs that correspond to GABA(A) receptors containing different subtypes of beta subunit. By using transgenic mice, we ascertained that alpha-CaMK-II increased IPSC amplitude but not the decay time by acting via beta2 subunit-containing GABA(A) receptors. In contrast, IPSC populations whose decay times were increased by alpha-CaMK-II were most likely mediated by beta3 subunit-containing receptors. Expressing alpha-CaMK-II with mutations that affected kinase function revealed that Ca(2+) and calmodulin binding is crucial for alpha-CaMK-II modulation of GABA(A) receptors, whereas kinase autophosphorylation is not. These findings have significant consequences for understanding the role of synaptic GABA(A) receptor heterogeneity within neurons and the precise regulation of inhibitory transmission by CaMK-II phosphorylation.

Citing Articles

UNC-43/CaMKII-triggered anterograde signals recruit GABARs to mediate inhibitory synaptic transmission and plasticity at C. elegans NMJs.

Hao Y, Liu H, Zeng X, Wang Y, Zeng W, Qian K Nat Commun. 2023; 14(1):1436.

PMID: 36918518 PMC: 10015018. DOI: 10.1038/s41467-023-37137-0.

Synaptic dysregulation and hyperexcitability induced by intracellular amyloid beta oligomers.

Fernandez-Perez E, Munoz B, Bascunan D, Peters C, Riffo-Lepe N, Espinoza M Aging Cell. 2021; 20(9):e13455.

PMID: 34409748 PMC: 8441418. DOI: 10.1111/acel.13455.

Regulation of GABA Receptors Induced by the Activation of L-Type Voltage-Gated Calcium Channels.

Gravielle M Membranes (Basel). 2021; 11(7).

PMID: 34209589 PMC: 8304739. DOI: 10.3390/membranes11070486.

Intricacies of GABA Receptor Function: The Critical Role of the β3 Subunit in Norm and Pathology.

Menzikov S, Morozov S, Kubatiev A Int J Mol Sci. 2021; 22(3).

PMID: 33535681 PMC: 7867123. DOI: 10.3390/ijms22031457.

Mechanisms of GABA receptor enhancement of extrasynaptic GABA receptor currents in cerebellar granule cells.

Khatri S, Wu W, Yang Y, Pugh J Sci Rep. 2019; 9(1):16683.

PMID: 31723152 PMC: 6853962. DOI: 10.1038/s41598-019-53087-4.

References

Thompson S, Wheat L, Brown N, Wingrove P, Pillai G, Whiting P . Salicylidene salicylhydrazide, a selective inhibitor of beta 1-containing GABAA receptors. Br J Pharmacol. 2004; 142(1):97-106. PMC: 1574914. DOI: 10.1038/sj.bjp.0705689. View

Nusser Z, Hajos N, Somogyi P, Mody I . Increased number of synaptic GABA(A) receptors underlies potentiation at hippocampal inhibitory synapses. Nature. 1998; 395(6698):172-7. DOI: 10.1038/25999. View

McDonald B, Moss S . Conserved phosphorylation of the intracellular domains of GABA(A) receptor beta2 and beta3 subunits by cAMP-dependent protein kinase, cGMP-dependent protein kinase protein kinase C and Ca2+/calmodulin type II-dependent protein kinase. Neuropharmacology. 1998; 36(10):1377-85. DOI: 10.1016/s0028-3908(97)00111-1. View

Wang Q, Liu L, Pei L, Ju W, Ahmadian G, Lu J . Control of synaptic strength, a novel function of Akt. Neuron. 2003; 38(6):915-28. DOI: 10.1016/s0896-6273(03)00356-8. View

McDonald B, Moss S . Differential phosphorylation of intracellular domains of gamma-aminobutyric acid type A receptor subunits by calcium/calmodulin type 2-dependent protein kinase and cGMP-dependent protein kinase. J Biol Chem. 1994; 269(27):18111-7. View

McDonald B, Amato A, Connolly C, Benke D, Moss S, Smart T . Adjacent phosphorylation sites on GABAA receptor beta subunits determine regulation by cAMP-dependent protein kinase. Nat Neurosci. 1999; 1(1):23-8. DOI: 10.1038/223. View

Herd M, Haythornthwaite A, Rosahl T, Wafford K, Homanics G, Lambert J . The expression of GABAA beta subunit isoforms in synaptic and extrasynaptic receptor populations of mouse dentate gyrus granule cells. J Physiol. 2007; 586(4):989-1004. PMC: 2375644. DOI: 10.1113/jphysiol.2007.146746. View

Brunig I, Scotti E, Sidler C, Fritschy J . Intact sorting, targeting, and clustering of gamma-aminobutyric acid A receptor subtypes in hippocampal neurons in vitro. J Comp Neurol. 2002; 443(1):43-55. DOI: 10.1002/cne.10102. View

Wei W, Zhang N, Peng Z, Houser C, Mody I . Perisynaptic localization of delta subunit-containing GABA(A) receptors and their activation by GABA spillover in the mouse dentate gyrus. J Neurosci. 2003; 23(33):10650-61. PMC: 6740905. View

10.

Houston C, Smart T . CaMK-II modulation of GABA(A) receptors expressed in HEK293, NG108-15 and rat cerebellar granule neurons. Eur J Neurosci. 2006; 24(9):2504-14. DOI: 10.1111/j.1460-9568.2006.05145.x. View

11.

Poisbeau P, Cheney M, Browning M, Mody I . Modulation of synaptic GABAA receptor function by PKA and PKC in adult hippocampal neurons. J Neurosci. 1999; 19(2):674-83. PMC: 6782188. View

12.

Laurie D, Seeburg P, Wisden W . The distribution of 13 GABAA receptor subunit mRNAs in the rat brain. II. Olfactory bulb and cerebellum. J Neurosci. 1992; 12(3):1063-76. PMC: 6576040. View

13.

DeLorey T, Handforth A, Anagnostaras S, Homanics G, Minassian B, Asatourian A . Mice lacking the beta3 subunit of the GABAA receptor have the epilepsy phenotype and many of the behavioral characteristics of Angelman syndrome. J Neurosci. 1998; 18(20):8505-14. PMC: 6792844. View

14.

Farrant M, Brickley S . Properties of GABA(A) receptor-mediated transmission at newly formed Golgi-granule cell synapses in the cerebellum. Neuropharmacology. 2003; 44(2):181-9. DOI: 10.1016/s0028-3908(02)00363-5. View

15.

Sur C, Wafford K, Reynolds D, Hadingham K, Bromidge F, Macaulay A . Loss of the major GABA(A) receptor subtype in the brain is not lethal in mice. J Neurosci. 2001; 21(10):3409-18. PMC: 6762474. View

16.

Ben-Ari Y, Gaiarsa J, Tyzio R, Khazipov R . GABA: a pioneer transmitter that excites immature neurons and generates primitive oscillations. Physiol Rev. 2007; 87(4):1215-84. DOI: 10.1152/physrev.00017.2006. View

17.

Brandon N, Jovanovic J, Colledge M, Kittler J, Brandon J, Scott J . A-kinase anchoring protein 79/150 facilitates the phosphorylation of GABA(A) receptors by cAMP-dependent protein kinase via selective interaction with receptor beta subunits. Mol Cell Neurosci. 2003; 22(1):87-97. DOI: 10.1016/s1044-7431(02)00017-9. View

18.

Weeber E, Jiang Y, Elgersma Y, Varga A, Carrasquillo Y, Brown S . Derangements of hippocampal calcium/calmodulin-dependent protein kinase II in a mouse model for Angelman mental retardation syndrome. J Neurosci. 2003; 23(7):2634-44. PMC: 6742065. View

19.

Jones M, Westbrook G . Shaping of IPSCs by endogenous calcineurin activity. J Neurosci. 1997; 17(20):7626-33. PMC: 6793922. View

20.

Huntsman M, Huguenard J . Fast IPSCs in rat thalamic reticular nucleus require the GABAA receptor beta1 subunit. J Physiol. 2006; 572(Pt 2):459-75. PMC: 1779681. DOI: 10.1113/jphysiol.2006.106617. View