Profile

Many hormones and neurotransmitters act on cell surface receptors to elevate cytosolic levels of soluble second messengers such as cyclic AMP and calcium. These molecules diffuse freely but the dynamics of second messenger generation and removal are such that their concentrations are only elevated locally and transiently. This spatial heterogeneity implies that cellular proteins that are sensitive to second messengers have discrete subcellular localization(s). The overall goal of this laboratory is to understand how localization of signal transduction molecules is achieved and how this impacts cellular regulation. Multiple synaptic roles for calcium/calmodulin-dependent protein kinase II (CaMKII) Neurons are highly asymmetric cells due to their extensive dendritic and axonal processes. Moreover, the dendrites are covered with thousands of dendritic spines that receive synaptic inputs from many different neurons. Each synapse can be independently modulated on time scales ranging from milliseconds to the lifetime of the animal. Of particular interest are long-term potentiation (LTP) and long-term depression (LTD) in the hippocampus, opposing forms of synaptic plasticity that are induced by calcium influx via NMDA-type glutamate receptors. High frequency stimulation of a synapse generally results in induction of LTP, where as low frequency stimulation induces LTD. Thus, calcium-dependent signaling molecules are able to generate different physiological responses depending on the frequency with which a synapse is stimulated. Furthermore, LTP and LTD are confined to synapse(s) that received the initial high or low frequency stimulation, respectively, without any “spill-over” to nearby unstimulated synapses. The major focus of this laboratory is to determine the molecular mechanisms that permit synapse specific generation of LTP or LTD. Calcium/calmodulin-dependent protein kinase II (CaMKII) plays a pivotal role in synaptic plasticity, learning and memory. CaMKII as an integrator of diverse calcium signals Dodecameric CaMKII holoenzymes require calcium and calmodulin for initial activation. Autophosphorylation at Thr286 converts the kinase to a form that has calcium/calmodulin-independent kinase activity, requiring a protein phosphatase to be inactivated. The activity of PP1γ1 targeted to the neuronal postsynaptic density by spinophilin and/or neurabin is believed to play a critical role in gating CaMKII autophosphorylation during synaptic plasticity. Thus, the opposing actions of calcium/calmodulin and protein phosphatases allow CaMKII to integrate information conveyed by the frequency, amplitude and duration of transient elevations of calcium that occur at synapses and induce LTP or LTD. In addition, it is very well established that Thr286 autophosphorylation is essential to normal synaptic plasticity, learning and memory. Mechanisms of CaMKII Targeting Our central hypothesis is that specific synaptic actions of CaMKII require the assembly of specific multiprotein complexes containing CaMKII and downstream mediators of individual signaling pathways, and are opposed by specific PP1 complexes. We are investigating several synaptic proteins that dynamically interact with CaMKII or PP1 by distinct biochemical mechanisms, including subunits of NMDA-type glutamate receptors and voltage-gated calcium channels, densin-180, alpha-actinin, spinophilin and neurabin, as well as some novel interactions. Our goal is to understand the biochemical/structural basis for these interactions and use this information to help us identify specific roles for these interactions in controlling synaptic function both physiologically (e.g., LTP/LTD) and pathologically (e.g., in Parkinson's Disease). These studies employ a diverse array of biochemical, molecular and cell biological, immunological, proteomic, fluorescent imaging and electrophysiological techniques.

Publications

The following timeline graph is generated from all co-authored publications.

Featured publications are shown below:

  1. Activated CaMKII Binds to the mGlu Metabotropic Glutamate Receptor and Modulates Calcium Mobilization. Marks CR, Shonesy BC, Wang X, Stephenson JR, Niswender CM, Colbran RJ (2018) Mol Pharmacol 94(6): 1352-1362
    › Primary publication · 30282777 (PubMed) · PMC6207916 (PubMed Central)
  2. Introduction to the Thematic Minireview Series: Brain glycogen metabolism. Carlson GM, Dienel GA, Colbran RJ (2018) J Biol Chem 293(19): 7087-7088
    › Primary publication · 29514979 (PubMed) · PMC5950002 (PubMed Central)
  3. Role of Striatal Direct Pathway 2-Arachidonoylglycerol Signaling in Sociability and Repetitive Behavior. Shonesy BC, Parrish WP, Haddad HK, Stephenson JR, Báldi R, Bluett RJ, Marks CR, Centanni SW, Folkes OM, Spiess K, Augustin SM, Mackie K, Lovinger DM, Winder DG, Patel S, Colbran RJ (2018) Biol Psychiatry 84(4): 304-315
    › Primary publication · 29458998 (PubMed) · PMC6023784 (PubMed Central)
  4. A novel mechanism for Ca/calmodulin-dependent protein kinase II targeting to L-type Ca channels that initiates long-range signaling to the nucleus. Wang X, Marks CR, Perfitt TL, Nakagawa T, Lee A, Jacobson DA, Colbran RJ (2017) J Biol Chem 292(42): 17324-17336
    › Primary publication · 28916724 (PubMed) · PMC5655510 (PubMed Central)
  5. The Atypical MAP Kinase SWIP-13/ERK8 Regulates Dopamine Transporters through a Rho-Dependent Mechanism. Bermingham DP, Hardaway JA, Refai O, Marks CR, Snider SL, Sturgeon SM, Spencer WC, Colbran RJ, Miller DM, Blakely RD (2017) J Neurosci 37(38): 9288-9304
    › Primary publication · 28842414 (PubMed) · PMC5607470 (PubMed Central)
  6. Densin-180 Controls the Trafficking and Signaling of L-Type Voltage-Gated Ca1.2 Ca Channels at Excitatory Synapses. Wang S, Stanika RI, Wang X, Hagen J, Kennedy MB, Obermair GJ, Colbran RJ, Lee A (2017) J Neurosci 37(18): 4679-4691
    › Primary publication · 28363979 (PubMed) · PMC5426563 (PubMed Central)
  7. Endocannabinoid signalling modulates susceptibility to traumatic stress exposure. Bluett RJ, Báldi R, Haymer A, Gaulden AD, Hartley ND, Parrish WP, Baechle J, Marcus DJ, Mardam-Bey R, Shonesy BC, Uddin MJ, Marnett LJ, Mackie K, Colbran RJ, Winder DG, Patel S (2017) Nat Commun : 14782
    › Primary publication · 28348378 (PubMed) · PMC5379055 (PubMed Central)
  8. Reduced bioavailable manganese causes striatal urea cycle pathology in Huntington's disease mouse model. Bichell TJV, Wegrzynowicz M, Tipps KG, Bradley EM, Uhouse MA, Bryan M, Horning K, Fisher N, Dudek K, Halbesma T, Umashanker P, Stubbs AD, Holt HK, Kwakye GF, Tidball AM, Colbran RJ, Aschner M, Neely MD, Di Pardo A, Maglione V, Osmand A, Bowman AB (2017) Biochim Biophys Acta Mol Basis Dis 1863(6): 1596-1604
    › Primary publication · 28213125 (PubMed) · PMC5515276 (PubMed Central)
  9. A Novel Human Mutation Disrupts Dendritic Morphology and Synaptic Transmission, and Causes ASD-Related Behaviors. Stephenson JR, Wang X, Perfitt TL, Parrish WP, Shonesy BC, Marks CR, Mortlock DP, Nakagawa T, Sutcliffe JS, Colbran RJ (2017) J Neurosci 37(8): 2216-2233
    › Primary publication · 28130356 (PubMed) · PMC5338762 (PubMed Central)
  10. CaMKII-mediated phosphorylation of GluN2B regulates recombinant NMDA receptor currents in a chloride-dependent manner. Tavalin SJ, Colbran RJ (2017) Mol Cell Neurosci : 45-52
    › Primary publication · 27998718 (PubMed) · PMC5315591 (PubMed Central)
  11. Changes in the Adult GluN2B Associated Proteome following Adolescent Intermittent Ethanol Exposure. Swartzwelder HS, Risher ML, Miller KM, Colbran RJ, Winder DG, Wills TA (2016) PLoS One 11(5): e0155951
    › Primary publication · 27213757 (PubMed) · PMC4877005 (PubMed Central)
  12. Thematic Minireview Series: Molecular Mechanisms of Synaptic Plasticity. Colbran RJ (2015) J Biol Chem 290(48): 28594-5
    › Primary publication · 26453312 (PubMed) · PMC4661373 (PubMed Central)
  13. Differential CaMKII regulation by voltage-gated calcium channels in the striatum. Pasek JG, Wang X, Colbran RJ (2015) Mol Cell Neurosci : 234-43
    › Primary publication · 26255006 (PubMed) · PMC4593756 (PubMed Central)
  14. Quantitative proteomics analysis of CaMKII phosphorylation and the CaMKII interactome in the mouse forebrain. Baucum AJ, Shonesy BC, Rose KL, Colbran RJ (2015) ACS Chem Neurosci 6(4): 615-31
    › Primary publication · 25650780 (PubMed) · PMC4609176 (PubMed Central)
  15. Evidence against dopamine D1/D2 receptor heteromers. Frederick AL, Yano H, Trifilieff P, Vishwasrao HD, Biezonski D, Mészáros J, Urizar E, Sibley DR, Kellendonk C, Sonntag KC, Graham DL, Colbran RJ, Stanwood GD, Javitch JA (2015) Mol Psychiatry 20(11): 1373-85
    › Primary publication · 25560761 (PubMed) · PMC4492915 (PubMed Central)
  16. The initiation of synaptic 2-AG mobilization requires both an increased supply of diacylglycerol precursor and increased postsynaptic calcium. Shonesy BC, Winder DG, Patel S, Colbran RJ (2015) Neuropharmacology : 57-62
    › Primary publication · 25484252 (PubMed) · PMC4312705 (PubMed Central)
  17. Genetic disruption of 2-arachidonoylglycerol synthesis reveals a key role for endocannabinoid signaling in anxiety modulation. Shonesy BC, Bluett RJ, Ramikie TS, Báldi R, Hermanson DJ, Kingsley PJ, Marnett LJ, Winder DG, Colbran RJ, Patel S (2014) Cell Rep 9(5): 1644-1653
    › Primary publication · 25466252 (PubMed) · PMC4268380 (PubMed Central)
  18. Inhibition of pancreatic β-cell Ca2+/calmodulin-dependent protein kinase II reduces glucose-stimulated calcium influx and insulin secretion, impairing glucose tolerance. Dadi PK, Vierra NC, Ustione A, Piston DW, Colbran RJ, Jacobson DA (2014) J Biol Chem 289(18): 12435-45
    › Primary publication · 24627477 (PubMed) · PMC4007438 (PubMed Central)
  19. CaMKII: a molecular substrate for synaptic plasticity and memory. Shonesy BC, Jalan-Sakrikar N, Cavener VS, Colbran RJ (2014) Prog Mol Biol Transl Sci : 61-87
    › Primary publication · 24484698 (PubMed)
  20. REEPing the benefits of an animal model of hereditary spastic paraplegia. Deutch AY, Hedera P, Colbran RJ (2013) J Clin Invest 123(10): 4134-6
    › Primary publication · 24051371 (PubMed) · PMC3784552 (PubMed Central)
  21. CaMKII regulates diacylglycerol lipase-α and striatal endocannabinoid signaling. Shonesy BC, Wang X, Rose KL, Ramikie TS, Cavener VS, Rentz T, Baucum AJ, Jalan-Sakrikar N, Mackie K, Winder DG, Patel S, Colbran RJ (2013) Nat Neurosci 16(4): 456-63
    › Primary publication · 23502535 (PubMed) · PMC3636998 (PubMed Central)
  22. Metabolic regulation of CaMKII protein and caspases in Xenopus laevis egg extracts. McCoy F, Darbandi R, Chen SI, Eckard L, Dodd K, Jones K, Baucum AJ, Gibbons JA, Lin SH, Colbran RJ, Nutt LK (2013) J Biol Chem 288(13): 8838-48
    › Primary publication · 23400775 (PubMed) · PMC3610959 (PubMed Central)
  23. Differential association of postsynaptic signaling protein complexes in striatum and hippocampus. Baucum AJ, Brown AM, Colbran RJ (2013) J Neurochem 124(4): 490-501
    › Primary publication · 23173822 (PubMed) · PMC3557548 (PubMed Central)
  24. Substrate-selective and calcium-independent activation of CaMKII by α-actinin. Jalan-Sakrikar N, Bartlett RK, Baucum AJ, Colbran RJ (2012) J Biol Chem 287(19): 15275-83
    › Primary publication · 22427672 (PubMed) · PMC3346149 (PubMed Central)
  25. Age-dependent targeting of protein phosphatase 1 to Ca2+/calmodulin-dependent protein kinase II by spinophilin in mouse striatum. Baucum AJ, Strack S, Colbran RJ (2012) PLoS One 7(2): e31554
    › Primary publication · 22348105 (PubMed) · PMC3278457 (PubMed Central)
  26. GluN2B subunit deletion reveals key role in acute and chronic ethanol sensitivity of glutamate synapses in bed nucleus of the stria terminalis. Wills TA, Klug JR, Silberman Y, Baucum AJ, Weitlauf C, Colbran RJ, Delpire E, Winder DG (2012) Proc Natl Acad Sci U S A 109(5): E278-87
    › Primary publication · 22219357 (PubMed) · PMC3277158 (PubMed Central)
  27. Loss of Thr286 phosphorylation disrupts synaptic CaMKIIα targeting, NMDAR activity and behavior in pre-adolescent mice. Gustin RM, Shonesy BC, Robinson SL, Rentz TJ, Baucum AJ, Jalan-Sakrikar N, Winder DG, Stanwood GD, Colbran RJ (2011) Mol Cell Neurosci 47(4): 286-92
    › Primary publication · 21627991 (PubMed) · PMC3149813 (PubMed Central)
  28. Characterization of a central Ca2+/calmodulin-dependent protein kinase IIalpha/beta binding domain in densin that selectively modulates glutamate receptor subunit phosphorylation. Jiao Y, Jalan-Sakrikar N, Robison AJ, Baucum AJ, Bass MA, Colbran RJ (2011) J Biol Chem 286(28): 24806-18
    › Primary publication · 21610080 (PubMed) · PMC3137056 (PubMed Central)
  29. Conformational changes underlying calcium/calmodulin-dependent protein kinase II activation. Hoffman L, Stein RA, Colbran RJ, Mchaourab HS (2011) EMBO J 30(7): 1251-62
    › Primary publication · 21343908 (PubMed) · PMC3094114 (PubMed Central)
  30. Tissue-specific variation of Ube3a protein expression in rodents and in a mouse model of Angelman syndrome. Gustin RM, Bichell TJ, Bubser M, Daily J, Filonova I, Mrelashvili D, Deutch AY, Colbran RJ, Weeber EJ, Haas KF (2010) Neurobiol Dis 39(3): 283-91
    › Primary publication · 20423730 (PubMed) · PMC2922926 (PubMed Central)
  31. Ca2+-dependent facilitation of Cav1.3 Ca2+ channels by densin and Ca2+/calmodulin-dependent protein kinase II. Jenkins MA, Christel CJ, Jiao Y, Abiria S, Kim KY, Usachev YM, Obermair GJ, Colbran RJ, Lee A (2010) J Neurosci 30(15): 5125-35
    › Primary publication · 20392935 (PubMed) · PMC2990970 (PubMed Central)
  32. Loss of GluN2B-containing NMDA receptors in CA1 hippocampus and cortex impairs long-term depression, reduces dendritic spine density, and disrupts learning. Brigman JL, Wright T, Talani G, Prasad-Mulcare S, Jinde S, Seabold GK, Mathur P, Davis MI, Bock R, Gustin RM, Colbran RJ, Alvarez VA, Nakazawa K, Delpire E, Lovinger DM, Holmes A (2010) J Neurosci 30(13): 4590-600
    › Primary publication · 20357110 (PubMed) · PMC2869199 (PubMed Central)
  33. CaV1.2 beta-subunit coordinates CaMKII-triggered cardiomyocyte death and afterdepolarizations. Koval OM, Guan X, Wu Y, Joiner ML, Gao Z, Chen B, Grumbach IM, Luczak ED, Colbran RJ, Song LS, Hund TJ, Mohler PJ, Anderson ME (2010) Proc Natl Acad Sci U S A 107(11): 4996-5000
    › Primary publication · 20194790 (PubMed) · PMC2841943 (PubMed Central)
  34. Identification and validation of novel spinophilin-associated proteins in rodent striatum using an enhanced ex vivo shotgun proteomics approach. Baucum AJ, Jalan-Sakrikar N, Jiao Y, Gustin RM, Carmody LC, Tabb DL, Ham AJ, Colbran RJ (2010) Mol Cell Proteomics 9(6): 1243-59
    › Primary publication · 20124353 (PubMed) · PMC2877984 (PubMed Central)
  35. Ca2+/calmodulin-dependent protein kinase II binds to and phosphorylates a specific SAP97 splice variant to disrupt association with AKAP79/150 and modulate alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type glutamate receptor (AMPAR) activity. Nikandrova YA, Jiao Y, Baucum AJ, Tavalin SJ, Colbran RJ (2010) J Biol Chem 285(2): 923-34
    › Primary publication · 19858198 (PubMed) · PMC2801293 (PubMed Central)
  36. CaMKII associates with CaV1.2 L-type calcium channels via selected beta subunits to enhance regulatory phosphorylation. Abiria SA, Colbran RJ (2010) J Neurochem 112(1): 150-61
    › Primary publication · 19840220 (PubMed) · PMC2814318 (PubMed Central)
  37. Association of protein phosphatase 1 gamma 1 with spinophilin suppresses phosphatase activity in a Parkinson disease model. Brown AM, Baucum AJ, Bass MA, Colbran RJ (2008) J Biol Chem 283(21): 14286-94
    › Primary publication · 18372251 (PubMed) · PMC2386916 (PubMed Central)
  38. Developmentally regulated alternative splicing of densin modulates protein-protein interaction and subcellular localization. Jiao Y, Robison AJ, Bass MA, Colbran RJ (2008) J Neurochem 105(5): 1746-60
    › Primary publication · 18248607 (PubMed) · PMC2814316 (PubMed Central)
  39. Selective targeting of the gamma1 isoform of protein phosphatase 1 to F-actin in intact cells requires multiple domains in spinophilin and neurabin. Carmody LC, Baucum AJ, Bass MA, Colbran RJ (2008) FASEB J 22(6): 1660-71
    › Primary publication · 18216290 (PubMed) · PMC2814319 (PubMed Central)
  40. Differential regulated interactions of calcium/calmodulin-dependent protein kinase II with isoforms of voltage-gated calcium channel beta subunits. Grueter CE, Abiria SA, Wu Y, Anderson ME, Colbran RJ (2008) Biochemistry 47(6): 1760-7
    › Primary publication · 18205403 (PubMed) · PMC2814322 (PubMed Central)
  41. Oxidation of calmodulin alters activation and regulation of CaMKII. Robison AJ, Winder DG, Colbran RJ, Bartlett RK (2007) Biochem Biophys Res Commun 356(1): 97-101
    › Primary publication · 17343827 (PubMed) · PMC1899527 (PubMed Central)
  42. L-type Ca2+ channel facilitation mediated by phosphorylation of the beta subunit by CaMKII. Grueter CE, Abiria SA, Dzhura I, Wu Y, Ham AJ, Mohler PJ, Anderson ME, Colbran RJ (2006) Mol Cell 23(5): 641-50
    › Primary publication · 16949361 (PubMed)
  43. Differential modulation of Ca2+/calmodulin-dependent protein kinase II activity by regulated interactions with N-methyl-D-aspartate receptor NR2B subunits and alpha-actinin. Robison AJ, Bartlett RK, Bass MA, Colbran RJ (2005) J Biol Chem 280(47): 39316-23
    › Primary publication · 16172120 (PubMed)
  44. Multivalent interactions of calcium/calmodulin-dependent protein kinase II with the postsynaptic density proteins NR2B, densin-180, and alpha-actinin-2. Robison AJ, Bass MA, Jiao Y, MacMillan LB, Carmody LC, Bartlett RK, Colbran RJ (2005) J Biol Chem 280(42): 35329-36
    › Primary publication · 16120608 (PubMed)
  45. Dopamine depletion alters phosphorylation of striatal proteins in a model of Parkinsonism. Brown AM, Deutch AY, Colbran RJ (2005) Eur J Neurosci 22(1): 247-56
    › Primary publication · 16029214 (PubMed) · PMC4819997 (PubMed Central)
  46. CaMKIIalpha enhances the desensitization of NR2B-containing NMDA receptors by an autophosphorylation-dependent mechanism. Sessoms-Sikes S, Honse Y, Lovinger DM, Colbran RJ (2005) Mol Cell Neurosci 29(1): 139-47
    › Primary publication · 15866054 (PubMed)
  47. Protein phosphatases and calcium/calmodulin-dependent protein kinase II-dependent synaptic plasticity. Colbran RJ (2004) J Neurosci 24(39): 8404-9
    › Primary publication · 15456812 (PubMed) · PMC6729910 (PubMed Central)
  48. Calcium/calmodulin-dependent protein kinase II and synaptic plasticity. Colbran RJ, Brown AM (2004) Curr Opin Neurobiol 14(3): 318-27
    › Primary publication · 15194112 (PubMed)
  49. A protein phosphatase-1gamma1 isoform selectivity determinant in dendritic spine-associated neurabin. Carmody LC, Bauman PA, Bass MA, Mavila N, DePaoli-Roach AA, Colbran RJ (2004) J Biol Chem 279(21): 21714-23
    › Primary publication · 15016827 (PubMed)
  50. Targeting of calcium/calmodulin-dependent protein kinase II. Colbran RJ (2004) Biochem J 378(Pt 1): 1-16
    › Primary publication · 14653781 (PubMed) · PMC1223945 (PubMed Central)