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. 2021 Aug 10;10:e64644. doi: 10.7554/eLife.64644

Figure 3. Linear activation of ERK by cAMP pathways.

(A) ppERK response to a single pulse of 0.5 μM cAMP is graded with duration. (B) Integral of ppERK concentration over time (AUC) in response to different cAMP concentrations (for 1 s) and different cAMP durations (with a concentration of 0.5 μM). (C) Time course of ppERK in response to single pulses of 0.1 μM Giβγ for different durations. Recruitment of ERK by Giβγ binding protein shows delayed activation. (D) Total activity of ppERK in response to different Giβγ concentrations (for 1 s) and durations (with a concentration of 0.1 μM). Increasing duration or concentration are similarly effective in increasing ppERK. (E) Direct and indirect cAMP pathways combine linearly for all duration inputs and sublinearly, with prolonged duration inputs. Two-way ANCOVA (analysis of covariance) of ppERK AUC versus stimulation characteristics (duration) and type (combination versus summation) as factors (N = 5 in each group) is significant for both duration and type (F (2,47) = 419.5, T < 0.001; P(dur) < 0.0001, T(dur) = 28.61, P(type) < 0.0001, T(type) = 4.54). Combo: response to Giβγ and cAMP, sum: sum of the responses in (A) and (C). (F) Ratio of ppERK to basal ppERK in response to cAMP activation of PKA, Epac or Giβγ (0.5 μM (cAMP) or 0.1 μM (Giβγ) for 30 s). ppERK increases quickly and transiently with Epac and with a delay and more prolonged in response to PKA or Giβγ.

Figure 3.

Figure 3—figure supplement 1. Time course of synaptic inputs for single-pulse simulations.

Figure 3—figure supplement 1.

(A) Calcium concentration. (A1) Three different concentrations of 1 s duration. (A2) Three different durations of 0.5 µM concentration. (B) cAMP concentration. cAMP decay is slower than calcium decay as observed experimentally. (B1) Three different concentrations of 1 s duration. (B2) Three different durations of 0.5 µM concentration. (C) Giβγ concentration. (C1) Three different concentrations of 1 s duration. (C2) Three different durations of 0.5 µM concentration.