Figure 8.

A working model of the proposed mechanism by which metabolic stress (↑ AMP/ATP ratio) “turns off” smooth muscle in the basal state (compare the control basal state, A, and the starved basal state, C), and inhibits stimulus-induced smooth muscle contraction (compare the control stimulated state, B, and the starved stimulated state, D). AMPK${\alpha }_2^{-/-}$ data revealed that constitutive AMPK reduces basal MLC phosphorylation, but how this is accomplished remains to be determined (A). Also, the precise role AMPK plays during muscle stimulation remains to be determined (B). Activation of AMPK by starvation (glucose and O₂ deprivation) increases basal Ca²⁺ sequestration into the sarcoplasmic reticulum (SR) by elevating PLB-pS16 levels, and increases basal rhoA-pS188 levels, reducing basal rhoA and ROCK activities, lowering basal levels of MYPT1-pT853 and cofilin-pS3 (C). Basal MYPT1-pT696 is also lowered, but the mechanism remains to be determined. During starvation, stimuli increase MLC-pS19, but not above the control basal level. This effect, plus a potentially lower ratio of filamentous-to-globular actin (F-actin/G-actin) due to the low cofilin-pS3 levels, prevents stimuli from causing a strong contraction. Reversal of metabolic stress re-establishes normal basal enzyme activities, permitting strong force development upon stimulation. Arrows = activation, circle and dashed line = inhibition. Line thickness indicates strength of connection (thicker = stronger).