Nair2015 - Interaction between neuromodulators via GPCRs - Effect on cAMP/PKA signaling (D2 Neuron)

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Model Identifier
BIOMD0000000636
Short description
Nair2015 - Interaction between neuromodulators via GPCRs - Effect on cAMP/PKA signaling (D2 Neuron)

This model is described in the article:

Nair AG, Gutierrez-Arenas O, Eriksson O, Vincent P, Hellgren Kotaleski J.
J. Neurosci. 2015 Oct; 35(41): 14017-14030

Abstract:

Transient changes in striatal dopamine (DA) concentration are considered to encode a reward prediction error (RPE) in reinforcement learning tasks. Often, a phasic DA change occurs concomitantly with a dip in striatal acetylcholine (ACh), whereas other neuromodulators, such as adenosine (Adn), change slowly. There are abundant adenylyl cyclase (AC) coupled GPCRs for these neuromodulators in striatal medium spiny neurons (MSNs), which play important roles in plasticity. However, little is known about the interaction between these neuromodulators via GPCRs. The interaction between these transient neuromodulator changes and the effect on cAMP/PKA signaling via Golf- and Gi/o-coupled GPCR are studied here using quantitative kinetic modeling. The simulations suggest that, under basal conditions, cAMP/PKA signaling could be significantly inhibited in D1R+ MSNs via ACh/M4R/Gi/o and an ACh dip is required to gate a subset of D1R/Golf-dependent PKA activation. Furthermore, the interaction between ACh dip and DA peak, via D1R and M4R, is synergistic. In a similar fashion, PKA signaling in D2+ MSNs is under basal inhibition via D2R/Gi/o and a DA dip leads to a PKA increase by disinhibiting A2aR/Golf, but D2+ MSNs could also respond to the DA peak via other intracellular pathways. This study highlights the similarity between the two types of MSNs in terms of high basal AC inhibition by Gi/o and the importance of interactions between Gi/o and Golf signaling, but at the same time predicts differences between them with regard to the sign of RPE responsible for PKA activation.Dopamine transients are considered to carry reward-related signal in reinforcement learning. An increase in dopamine concentration is associated with an unexpected reward or salient stimuli, whereas a decrease is produced by omission of an expected reward. Often dopamine transients are accompanied by other neuromodulatory signals, such as acetylcholine and adenosine. We highlight the importance of interaction between acetylcholine, dopamine, and adenosine signals via adenylyl-cyclase coupled GPCRs in shaping the dopamine-dependent cAMP/PKA signaling in striatal neurons. Specifically, a dopamine peak and an acetylcholine dip must interact, via D1 and M4 receptor, and a dopamine dip must interact with adenosine tone, via D2 and A2a receptor, in direct and indirect pathway neurons, respectively, to have any significant downstream PKA activation.

To the extent possible under law, all copyright and related or neighbouring rights to this encoded model have been dedicated to the public domain worldwide. Please refer to CC0 Public Domain Dedication for more information.

Format
SBML (L2V4)
Related Publication
  • Sensing Positive versus Negative Reward Signals through Adenylyl Cyclase-Coupled GPCRs in Direct and Indirect Pathway Striatal Medium Spiny Neurons.
  • Nair AG, Gutierrez-Arenas O, Eriksson O, Vincent P, Hellgren Kotaleski J
  • The Journal of neuroscience : the official journal of the Society for Neuroscience , 10/ 2015 , Volume 35 , pages: 14017-14030 , PubMed ID: 26468202
  • Science for Life Laboratory, School of Computer Science and Communication, KTH Royal Institute of Technology, 11428 Stockholm, Sweden, Manipal University, 576104 Manipal, India.
  • Transient changes in striatal dopamine (DA) concentration are considered to encode a reward prediction error (RPE) in reinforcement learning tasks. Often, a phasic DA change occurs concomitantly with a dip in striatal acetylcholine (ACh), whereas other neuromodulators, such as adenosine (Adn), change slowly. There are abundant adenylyl cyclase (AC) coupled GPCRs for these neuromodulators in striatal medium spiny neurons (MSNs), which play important roles in plasticity. However, little is known about the interaction between these neuromodulators via GPCRs. The interaction between these transient neuromodulator changes and the effect on cAMP/PKA signaling via Golf- and Gi/o-coupled GPCR are studied here using quantitative kinetic modeling. The simulations suggest that, under basal conditions, cAMP/PKA signaling could be significantly inhibited in D1R+ MSNs via ACh/M4R/Gi/o and an ACh dip is required to gate a subset of D1R/Golf-dependent PKA activation. Furthermore, the interaction between ACh dip and DA peak, via D1R and M4R, is synergistic. In a similar fashion, PKA signaling in D2+ MSNs is under basal inhibition via D2R/Gi/o and a DA dip leads to a PKA increase by disinhibiting A2aR/Golf, but D2+ MSNs could also respond to the DA peak via other intracellular pathways. This study highlights the similarity between the two types of MSNs in terms of high basal AC inhibition by Gi/o and the importance of interactions between Gi/o and Golf signaling, but at the same time predicts differences between them with regard to the sign of RPE responsible for PKA activation.Dopamine transients are considered to carry reward-related signal in reinforcement learning. An increase in dopamine concentration is associated with an unexpected reward or salient stimuli, whereas a decrease is produced by omission of an expected reward. Often dopamine transients are accompanied by other neuromodulatory signals, such as acetylcholine and adenosine. We highlight the importance of interaction between acetylcholine, dopamine, and adenosine signals via adenylyl-cyclase coupled GPCRs in shaping the dopamine-dependent cAMP/PKA signaling in striatal neurons. Specifically, a dopamine peak and an acetylcholine dip must interact, via D1 and M4 receptor, and a dopamine dip must interact with adenosine tone, via D2 and A2a receptor, in direct and indirect pathway neurons, respectively, to have any significant downstream PKA activation.
Contributors
Anu G Nair

Metadata information

is
BioModels Database MODEL1502200001
BioModels Database BIOMD0000000636
isDescribedBy
PubMed 26468202
hasTaxon
Taxonomy Mus musculus
hasProperty

Curation status
Curated


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  • Model originally submitted by : Anu G Nair
  • Submitted: Feb 20, 2015 11:19:40 AM
  • Last Modified: May 16, 2017 2:20:10 PM
Revisions
  • Version: 2 public model Download this version
    • Submitted on: May 16, 2017 2:20:10 PM
    • Submitted by: Anu G Nair
    • With comment: Current version of Nair2015 - Interaction between neuromodulators via GPCRs - Effect on cAMP/PKA signaling (D2 Neuron)
  • Version: 1 public model Download this version
    • Submitted on: Feb 20, 2015 11:19:40 AM
    • Submitted by: Anu G Nair
    • With comment: Original import of D2 Neuron Model

(*) You might be seeing discontinuous revisions as only public revisions are displayed here. Any private revisions unpublished model revision of this model will only be shown to the submitter and their collaborators.

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Species
Reactions
Reactions Rate Parameters
mwa2c44a01_28c9_4dbd_b034_364f9b5b6cc3 + mw7df45520_98cc_4c0b_91a7_c6e7297de98a => mwed1b3928_8d78_44d1_aee7_9d11d6437cfc mw26af457f_7462_4410_a392_e0bbb6071ea5*(mw1ef56a9a_9d9b_4490_8fcd_53b7e50bf5d6*mwa2c44a01_28c9_4dbd_b034_364f9b5b6cc3*mw7df45520_98cc_4c0b_91a7_c6e7297de98a-mw6ae3f7a6_bf58_475e_930e_6bf7a79f3761*mwed1b3928_8d78_44d1_aee7_9d11d6437cfc) mw6ae3f7a6_bf58_475e_930e_6bf7a79f3761 = 5.0; mw1ef56a9a_9d9b_4490_8fcd_53b7e50bf5d6 = 50.0
mw68d3f409_9462_4515_8c07_bc105fa0eaf1 + mw081c9f7b_011e_440f_971d_d0316d2a1e6c => mwe8cc261d_af39_4e88_8a65_a4994dcea2ff mw26af457f_7462_4410_a392_e0bbb6071ea5*(mw690a2134_fb59_4061_be3b_929335ef629b*mw68d3f409_9462_4515_8c07_bc105fa0eaf1*mw081c9f7b_011e_440f_971d_d0316d2a1e6c-mwc0a23657_7f6c_4e0d_9f11_06b3ab5126f0*mwe8cc261d_af39_4e88_8a65_a4994dcea2ff) mw690a2134_fb59_4061_be3b_929335ef629b = 0.005; mwc0a23657_7f6c_4e0d_9f11_06b3ab5126f0 = 0.3
mw2f3e9c55_e57f_416e_b4b1_cc49a26192c0 + mw4855b1cd_d7bc_4072_9736_dca30bbe448d => mwcf1bb70c_9d0b_4e82_b58a_6f8e73208af9 mw26af457f_7462_4410_a392_e0bbb6071ea5*(mwa390f769_ebf1_4023_8af0_1c00e2a9bf82*mw2f3e9c55_e57f_416e_b4b1_cc49a26192c0*mw4855b1cd_d7bc_4072_9736_dca30bbe448d-mw0beb6cc4_36bd_4022_8993_29f981652ebe*mwcf1bb70c_9d0b_4e82_b58a_6f8e73208af9) mwa390f769_ebf1_4023_8af0_1c00e2a9bf82 = 0.005; mw0beb6cc4_36bd_4022_8993_29f981652ebe = 1.0
mwcf1bb70c_9d0b_4e82_b58a_6f8e73208af9 => mw24435476_9c30_4878_b26f_4b3c5a0685c6 + mw4855b1cd_d7bc_4072_9736_dca30bbe448d mw26af457f_7462_4410_a392_e0bbb6071ea5*mw62c51fcf_c107_4d3c_849e_9b168df54490*mwcf1bb70c_9d0b_4e82_b58a_6f8e73208af9 mw62c51fcf_c107_4d3c_849e_9b168df54490 = 7.0
mwa9e7a93f_2393_4220_9ac8_79a02d068dc3 => mw24435476_9c30_4878_b26f_4b3c5a0685c6 + mw522cacf1_5e61_4b95_8742_cf61cb824893 mw26af457f_7462_4410_a392_e0bbb6071ea5*mwdcc4ce84_732d_4f5b_84e2_e5b93617200b*mwa9e7a93f_2393_4220_9ac8_79a02d068dc3 mwdcc4ce84_732d_4f5b_84e2_e5b93617200b = 0.2
mwbe974953_e869_4622_b4a8_745555c8d7fd = ModelValue_139+ModelValue_147*(ModelValue_140-ModelValue_139)*Adnpeak [] ModelValue_147 = 0.0; Adnpeak = 0.0; ModelValue_139 = 150.0; ModelValue_140 = 1000.0
mw6e845d87_603e_4463_874d_866f554303df => mw3d9e6efb_8e12_49c9_a87f_e067914b951d + mw9710c658_a2a1_4f49_b494_af109853f251 mw26af457f_7462_4410_a392_e0bbb6071ea5*mwf633f298_303f_46d1_b644_ae07ae366f45*mw6e845d87_603e_4463_874d_866f554303df mwf633f298_303f_46d1_b644_ae07ae366f45 = 3.0
A2AR + mw351f6cee_3e64_4b8e_8e60_24b1aca99a92 => mw0b46978f_b522_4cde_97f0_574cd7dbbae7 mw26af457f_7462_4410_a392_e0bbb6071ea5*(mw448bd49f_40ad_46c9_81f6_3494057dc37d*A2AR*mw351f6cee_3e64_4b8e_8e60_24b1aca99a92-mwa466eec8_9bc0_44d5_8027_d5925b378429*mw0b46978f_b522_4cde_97f0_574cd7dbbae7) mwa466eec8_9bc0_44d5_8027_d5925b378429 = 1.0; mw448bd49f_40ad_46c9_81f6_3494057dc37d = 0.005
mwbae3bd11_0ab4_4587_a931_9c5dc5e777ba => mw1c97b02d_169a_4eb8_bc84_1be57c51a255 + mw42919ead_5972_4151_85ac_fcc88ca105a6 mw26af457f_7462_4410_a392_e0bbb6071ea5*mwb0a6bd5e_87a0_425c_a5c7_ea69903e0bf3*mwbae3bd11_0ab4_4587_a931_9c5dc5e777ba mwb0a6bd5e_87a0_425c_a5c7_ea69903e0bf3 = 10.0
mw2badefa3_32e8_4b66_9e69_245d9ec74e33 => mw42919ead_5972_4151_85ac_fcc88ca105a6 + mw9bcba6bc_9788_4f7f_afb5_1c8f3b33c3d1 mw26af457f_7462_4410_a392_e0bbb6071ea5*mwcabc0868_2435_4850_964b_e3ddee39f5ad*mw2badefa3_32e8_4b66_9e69_245d9ec74e33 mwcabc0868_2435_4850_964b_e3ddee39f5ad = 30.0
mw46dccec6_6f0f_40f6_a10c_2f34ae7a005a + mw29ba9e7c_6865_4817_8775_be2dbc29651e => mw2075d2cf_955e_4150_98b8_847103c53845 mw26af457f_7462_4410_a392_e0bbb6071ea5*(mw541807fb_7d9f_4788_9f21_cc62846b5826*mw46dccec6_6f0f_40f6_a10c_2f34ae7a005a*mw29ba9e7c_6865_4817_8775_be2dbc29651e-mwb494aae2_da19_4ac0_96e2_0dcd9440edc2*mw2075d2cf_955e_4150_98b8_847103c53845) mwb494aae2_da19_4ac0_96e2_0dcd9440edc2 = 1.0; mw541807fb_7d9f_4788_9f21_cc62846b5826 = 6.25E-5
mw2075d2cf_955e_4150_98b8_847103c53845 => mw1c97b02d_169a_4eb8_bc84_1be57c51a255 + mw29ba9e7c_6865_4817_8775_be2dbc29651e mw26af457f_7462_4410_a392_e0bbb6071ea5*mwe4474191_0c92_406c_a6f5_4a167f541d36*mw2075d2cf_955e_4150_98b8_847103c53845 mwe4474191_0c92_406c_a6f5_4a167f541d36 = 0.25
mw1c97b02d_169a_4eb8_bc84_1be57c51a255 + mw29ba9e7c_6865_4817_8775_be2dbc29651e => mw2075d2cf_955e_4150_98b8_847103c53845 mw26af457f_7462_4410_a392_e0bbb6071ea5*mw17d612a2_c9d5_4251_8122_5f037fc630e3*mw1c97b02d_169a_4eb8_bc84_1be57c51a255*mw29ba9e7c_6865_4817_8775_be2dbc29651e mw17d612a2_c9d5_4251_8122_5f037fc630e3 = 0.00105
mw29ba9e7c_6865_4817_8775_be2dbc29651e => mw724f1afe_8032_40ae_96ca_808ab7b8b943 + mw9bcba6bc_9788_4f7f_afb5_1c8f3b33c3d1 mw26af457f_7462_4410_a392_e0bbb6071ea5*mwcabc0868_2435_4850_964b_e3ddee39f5ad*mw29ba9e7c_6865_4817_8775_be2dbc29651e mwcabc0868_2435_4850_964b_e3ddee39f5ad = 30.0
mwd794c746_c826_4ba1_9e09_a9d1e122d925 => mw29ba9e7c_6865_4817_8775_be2dbc29651e + mwfed0682b_39f1_4b09_94e8_c45a51744092 mw26af457f_7462_4410_a392_e0bbb6071ea5*mw8db06baf_d8bb_4a1a_b415_2d51fa1e53ba*mwd794c746_c826_4ba1_9e09_a9d1e122d925 mw8db06baf_d8bb_4a1a_b415_2d51fa1e53ba = 0.25
Curator's comment:
(added: 02 May 2017, 16:53:54, updated: 02 May 2017, 16:53:54)
We reproduced figure 5C from the paper using COPASI and created the plot using Matplotlib.