Elucidation of molecular kinetic schemes from macroscopic traces using system identification
Fig 8
Molecular kinetic scheme of crosstalk signaling in the mGluR2/5-HT2AR heteromeric complex in response to glutamate antipsychotics.
(A) (Top) Scheme of crosstalk signaling through the mGluR2/5-HT2AR complex. In response to the endogenous ligands glutamate and serotonin, the mGluR2/5-HT2AR complex signals through Gi and Gq signaling pathways respectively. Certain ligands such as LY379268, a dominant mGluR2 agonist with antipsychotic properties, are able to crosstalk through the complex and activate both Gi and Gq. (Bottom) Molecular kinetic schemes associated with the cis-activation and the trans-activation theories of crosstalk. (B) (Left) Representative G-protein sensitive ion-channel (GIRK4*) current trace (output) elicited by a step in LY379268 concentration from 0 to 1 μM (input). (Right) Molecular kinetic scheme obtained by applying SYSMOLE to the traces. (C) Fractional occupancies as a function of time of the four states in the molecular kinetic scheme: Gi OFF / Gq OFF, Gi ON / Gq OFF, Gi ON / Gq ON, and Gi OFF / Gq ON. The molecular kinetic scheme postulates a new state Gi OFF / Gq ON and supports the trans-activation theory for crosstalk through the complex (see Results section). Simulations were generated with the mean value of the kinetic parameters (N = 5 traces). Kinetic parameter values can be found on Table 2.