Activator of G protein signaling (AGS)-3 plays functional roles in cell division, synaptic plasticity, addictive behavior, and neuronal development. As part of a broad effort to define the extent of functional diversity of AGS3-regulated-events in vivo, we generated AGS3 null mice. Surprisingly, AGS3 null adult mice exhibited unexpected alterations in cardiovascular and metabolic functions without any obvious changes in motor skills, basic behavioral traits, and brain morphology. AGS3 null mice exhibited a lean phenotype, reduced fat mass, and increased nocturnal energy expenditure. AGS3 null mice also exhibited altered blood pressure control mechanisms. These studies expand the functional repertoire for AGS3 and other G protein regulatory proteins providing unexpected mechanisms by which G protein systems may be targeted to influence obesity and cardiovascular function.
Summary. Rats were randomly assigned to treatments: (i) no surgery control; (ii) saline control; (iii) 0\m=.\25,0\m=.\5,1\ m=.\0or 2\m=.\0 \g=m\gnifedipine kg\m=-\1mi n\m=-\1; or (iv) 5\m=.\0 \g=m\g ritodrine kg\m=-\1 min\m=-\1. All drug treatments increased the interval between pup deliveries compared with the no surgery and saline controls. Apparent complete tocolysis was observed in 20, 60, 80 and 80% of the animals receiving 0\m=.\5, 1\m=.\0or 2\m=.\0 \ g=m\ gnifedipine kg\m=-\1 min\m=-\ 1 or 5 \ m=. \ 0\ g=m\ g ritodrine kg\ m=-\ 1 mi n\m=-\1, respectively. A positive pharmacodynamic relationship was observed for the nifedipine doses. Analysis of pup viability showed no statistically significant difference among treatments. Treatment with 2\m=.\0 \g=m\gnifedipine kg\m=-\1 min\m=-\ 1 gave a delay in pup delivery comparable to that with ritodrine.
Activator of G‐protein Signaling (AGS) 3 and AGS5/LGN, via regulation of G‐protein signaling, play central functional roles in cell division, synaptic plasticity, addictive behavior and/or neuronal development. As part of a broad effort to define the extent of functional diversity of AGS regulated‐events in vivo, we present this report on AGS3 null mice. Surprisingly, AGS3 null adult mice exhibited unexpected alterations in cardiovascular and metabolic functions, without any obvious changes in basic behavioral traits or gross brain morphology. Despite higher food consumption AGS3−/− mice deposited significantly less fat than wild type mice, primarily due to higher rates of nocturnal energy expenditure. Conscious, unrestrained AGS3−/− mice exhibited significantly lower arterial pressures and reduced diurnal variations in arterial pressure that are associated with increased baroreceptor reflex sensitivity and a failure to adequately compensate to the decrease in arterial pressure elicited by the vasodilator sodium nitroprusside. These studies expand the functional repertoire for AGS3 and other GPR proteins providing unexpected venues for the development of therapeutic agents to influence obesity and cardiovascular regulation.
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