Age Increases Cardiac Gαi2 Expression, Resulting in Enhanced Coupling to G Protein-coupled Receptors

Kilts, Jason D.; Akazawa, Toshimasa; Richardson, Mark D.; Kwatra, Madan M.

doi:10.1074/jbc.m203640200

Cited by 42 publications

(20 citation statements)

References 66 publications

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“…The effects of aging in cAMP accumulation in other preparations show impairment of the activity of the catalytic subunit of adenylate cyclase in rats (Kilts et al 2002) and in the heart of >60-yearold humans (Brodde et al 1995). However, it has been described that the maximal ability of forskolin to increase cAMP in the adrenal medulla and liver is enhanced in 24-month-old rats (Tumer et al 1996).…”

Section: Discussionmentioning

confidence: 99%

Carotid body function in aged rats: responses to hypoxia, ischemia, dopamine, and adenosine

Monteiro

Batuca

Obeso

et al. 2010

AGE

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The carotid body (CB) is the main arterial chemoreceptor with a low threshold to hypoxia. CB activity is augmented by A 2 -adenosine receptors stimulation and attenuated by D 2 -dopamine receptors. The effect of aging on ventilatory responses mediated by the CB to hypoxia, ischemia, and to adenosine and dopamine administration is almost unknown. This study aims to investigate the ventilatory response to ischemia and to adenosine, dopamine, and their antagonists in old rats, as well as the effect of hypoxia on adenosine 3′,5′-cyclic monophosphate (cAMP) accumulation in the aged CB. In vivo experiments were performed on young and aged rats anesthetized with pentobarbitone and breathing spontaneously. CB ischemia was induced AGE (2011) 33:337-350 DOI 10.1007 Scientific knowledge on the subject The functional ventilatory consequences of the morphological and molecular changes in the carotid body observed in aged animals, as well as the ventilatory effects of dopamine and adenosine in old animals, are still unknown.What this study adds to the field The carotid body's peripheral control of ventilation is not impaired by aging. The preservation of the inhibitory and excitatory effects on ventilation caused by exogenous dopamine and adenosine, respectively, should be taken into account in the therapeutic use of these amines and their agonists and antagonists in elderly people. by bilateral common carotid occlusions. cAMP content was measured in CB incubated with different oxygen concentrations. Hyperoxia caused a decrease in cAMP in the CB at all ages, but no differences were found between normoxia and hypoxia or between young and old animals. The endogenous dopaminergic inhibitory tonus is slightly reduced. However, both the ventilation decrease caused by exogenous dopamine and the increase mediated by A 2A -adenosine receptors are not impaired in aged animals. The bradycardia induced by adenosine is attenuated in old rats. The CB's peripheral control of ventilation is preserved during aging. Concerns have also arisen regarding the clinical usage of adenosine to revert supraventricular tachycardia and the use of dopamine in critical care situations involving elderly people.

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Section: Discussionmentioning

confidence: 99%

Carotid body function in aged rats: responses to hypoxia, ischemia, dopamine, and adenosine

Monteiro

Batuca

Obeso

et al. 2010

AGE

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“…First, the alterations in receptor binding and AC biomarkers ranged up to about 20%; this is approximately the magnitude of the changes evoked by CPF in the developing brain (Aldridge et al 2004;Meyer et al 2003;Song et al 1997), by other defined neurotoxicants such as nicotine (Slotkin et al 1992), or by the loss of function associated with aging (Fraeyman et al 2000;Kilts et al 2002). Relatively small changes have important functional consequences because the AC pathway amplifies receptor signals by orders of magnitude: the activation of a single AC molecule leads to the production of numerous cAMP molecules and consequent activation of protein kinase A, which in turn elicits a plethora of downstream phosphorylation events (Freissmuth et al 1989;Gilman 1989;Stiles 1989;Weiss et al 1988).…”

Section: Discussionmentioning

confidence: 99%

Developmental effects of chlorpyrifos extend beyond neurotoxicity: critical periods for immediate and delayed-onset effects on cardiac and hepatic cell signaling.

Meyer

Seidler

Slotkin

2004

Environ Health Perspect

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The fetal and neonatal neurotoxicity of chlorpyrifos (CPF) and related insecticides is a major concern. Developmental effects of CPF involve mechanisms over and above cholinesterase inhibition, notably events in cell signaling that are shared by nonneural targets. In the present study, we evaluated the immediate and long-term effects of CPF exposure of rats during different developmental windows [gestational days (GD) 9-12 or 17-20, postnatal days (PN) 1-4 or 11-14] on the adenylyl cyclase (AC) signaling cascade in the heart and liver. In addition to basal AC activity, we assessed the responses to direct AC stimulants (forskolin, Mn 2+ ); to isoproterenol and glucagon, which activate signaling through specific membrane receptors; and to sodium fluoride, which activates the G-proteins that couple the receptors to AC. Few immediate effects on AC were apparent when CPF doses remained below the threshold for systemic toxicity. Nevertheless, CPF exposures on GD9-12, GD17-20, or PN1-4 elicited sex-selective effects that emerged by adulthood (PN60), whereas later exposure (PN11-14) elicited smaller, nonsignificant effects, indicative of closure of the window of vulnerability. Most of the effects were heterologous, involving signaling elements downstream from the receptors, and thus were shared by multiple inputs; superimposed on this basic pattern, there were also selective alterations in receptor-mediated responses. These results suggest that the developmental toxicity of CPF extends beyond the nervous system, to include cell signaling cascades that are vital to cardiac and hepatic homeostasis. Future work needs to address the potential implications of these effects for cardiovascular and metabolic disorders that may emerge long after the end of CPF exposure.

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“…Previous reports of age-related alterations in this signal transduction pathway are inconsistent and appear to be tissue and G-protein-type dependent. For example, recent data describe significant alterations in the G s and G i /alpha subunit complex of the adrenergic pathways in aged cardiac tissue and brains from Alzheimer-type dementia, but such alterations do not appear in brains without specific pathology (12,19,20). Although we are unaware of data documenting age-related alterations to the G i protein-dependent pathway of signal transduction within neurons from the PVN, some reports suggest disruption in this pathway in aged cells isolated from liver, kidney, and bladder (8,10).…”

Section: Discussionmentioning

confidence: 99%

Reduced feeding response to muscimol and neuropeptide Y in senescent F344 rats

Coppola

Horwitz

Hamilton

et al. 2005

American Journal of Physiology-Regulatory, Integrative and Comp

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(NPY). In the present study, we tested the hypothesis that responsiveness to GABA, a putative potentiator of NPY's effect, is also diminished. Young and old male F344 rats received injections of NPY, muscimol, (MUS, a GABA-A receptor agonist), combinations of these two agents, and vehicle [artificial cerebrospinal fluid (aCSF)] into the hypothalamic paraventricular nucleus (PVN). Both young and old presenescent rats increased their food intake in response to NPY, MUS, and the combination of the two (in comparison to injections of aCSF). The combination treatment was generally more effective than either NPY or MUS alone. These data are consistent with suggestions that both NPY and GABA play a role in the regulation of feeding behavior. Senescent rats exhibited an attenuated NPY-induced food intake, no increase in response to MUS, and a response to NPY ϩ MUS that was no larger than that of NPY alone. We conclude that PVN injections of GABA, as well as NPY, are less effective in stimulating feeding in senescent rats and suggest that alterations in their signaling pathways play a role in the involuntary feeding decrease seen near the end of life.anorexia of aging; brain; food intake control; hypothalamus WE HAVE PREVIOUSLY SHOWN that old rats undergo rapid and spontaneous declines in food intake and body weight near the end of their lives (3, 4, 11). Reductions of food intake and body weight are two of several biochemical/physiological functional changes in these old rats. The combined alterations are part of a distinct stage of life that we, and others, define as senescent because the animals are no longer thriving, but rather, are progressing rapidly toward death (9,16,21). The factors underlying entry into senescence or the declines in physiological function have yet to be elucidated. In a series of previous studies, we focused on mechanisms that may be responsible for the inability of senescent animals to maintain their body weight. We found that the body weight loss of senescent male F344 rats involves a reduction in food intake (4), that this reduction is accompanied by diminished responsiveness to intracerebroventricular injections of neuropeptide Y (NPY), a strong stimulator of food intake (3), and that neither the expression of NPY Y1 nor Y5 receptors in the hypothalamic paraventricular nucleus (PVN), a major site of NPY stimulation of feeding, nor the number of PVN neurons containing Y1 protein differ in senescent vs. presenescent rats (7). One possible explanation for the blunted responsiveness of the senescent rats to NPY, despite no apparent reduction in receptors, is altered modulation of the NPY action by other neuropeptides and/or neurotransmitters. For example, GABA is colocalized with NPY (1, 6, 13), and it has been suggested that under some circumstances, they may be released together (15,17). Previous investigations have shown that GABA and GABA agonists were only mild stimulants of food intake in the absence of NPY; however, administration of the GABA-A receptor agonist muscimol (MUS) with NPY ...

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Age Increases Cardiac Gαi2 Expression, Resulting in Enhanced Coupling to G Protein-coupled Receptors

Cited by 42 publications

References 66 publications

Carotid body function in aged rats: responses to hypoxia, ischemia, dopamine, and adenosine

Carotid body function in aged rats: responses to hypoxia, ischemia, dopamine, and adenosine

Developmental effects of chlorpyrifos extend beyond neurotoxicity: critical periods for immediate and delayed-onset effects on cardiac and hepatic cell signaling.

Reduced feeding response to muscimol and neuropeptide Y in senescent F344 rats

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