Adenylyl cyclase activity in Alzheimer's disease brain: stimulatory and inhibitory signal transduction pathways are differently affected

Background: During aging and in age-associated disorders, such as Alzheimer's Disease (AD), learning abilities decline. Probably, disturbances in signal transduction in brain cells underlie the cognitive decline. The phosphorylation/dephosphorylation imbalance occurring in degenerating neurons was recently related to abnormal activity of one or more signal transduction pathways. AD is known to be associated with altered neuronal Ca2+ homeostasis, as Ca2+ accumulates in affected neurons leading to functional impairment. It is becoming more and more evident the involvement of signal transduction pathways acting upon Ca2+ metabolism and phosphorylation regulation of proteins. A growing interest raised around the role of signal transduction systems in a number of human diseases including neurodegenerative diseases, with special regard to the systems related to the phosphoinositide (PI) pathway and AD. The PI signal transduction pathway plays a crucial role, being involved in a variety of cell functions, such as hormone secretion, neurotransmitter signal transduction, cell growth, membrane trafficking, ion channel activity, cytoskeleton regulation, cell cycle control, apoptosis, cell and tissue polarity, and contributes to regulate the Ca2+ levels in the nervous tissue. Conclusion: A number of observations indicated that PI-specific phospholipase C (PLC) enzymes might be involved in the alteration of neurotransmission. To understand the role and the timing of action of the signalling pathways recruited during the brain morphology changes during the AD progression might help to elucidate the aetiopathogenesis of the disease, paving the way to prognosis refinement and/or novel molecular therapeutic strategies.

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709 Adenylyl cyclase signal transduction in Alzheimer's disease lymphocytes

Neurobiology of Aging ◽

10.1016/s0197-4580(96)80711-1 ◽

1996 ◽

Vol 17 (4) ◽

pp. S176

Author(s):

A. Garlind ◽

R.F. Cowburn ◽

B. Winblad

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Signal Transduction ◽

Adenylyl Cyclase

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TNF-alpha inhibits isoproterenol-stimulated adenylyl cyclase activity in cultured airway smooth muscle cells

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.1997.272.4.l644 ◽

1997 ◽

Vol 272 (4) ◽

pp. L644-L650 ◽

Cited By ~ 8

Author(s):

C. W. Emala ◽

J. Kuhl ◽

C. L. Hungerford ◽

C. A. Hirshman

Keyword(s):

Signal Transduction ◽

Smooth Muscle ◽

Adenylyl Cyclase ◽

Airway Smooth Muscle ◽

Adrenergic Receptor ◽

Cyclase Activity ◽

Tnf Alpha ◽

Adenylyl Cyclase Activity ◽

Beta Adrenergic Receptor ◽

Beta Adrenergic

Inflammation, increased cytokine production, and decreased responsiveness of airway smooth muscle (ASM) to beta-adrenergic agonists are characteristics of asthma. We questioned whether the cytokine tumor necrosis factor-alpha (TNF-alpha) directly impaired beta-adrenergic signal transduction in cultured canine ASM cells. Confluent ASM cells exposed to TNF-alpha (0.1-10 ng/ml) for 72 h showed lower maximal levels of adenylyl cyclase activity in response to isoproterenol (10 ng/ml; 14 +/- 4.3 vs. 7.5 +/- 1.3 pmol adenosine 3',5'-cyclic monophosphate x well(-1) x 20 min(-1), control vs. treated, respectively), despite no changes in beta-adrenergic receptor numbers (maximum number of binding sites = 4.8 +/- 0.72 vs. 4.5 +/- 0.81 fmol/mg protein, control vs. treated, respectively). Adenylyl cyclase activities in response to prostaglandin E1, NaF, or forskolin were not different in treated and untreated cells. These results demonstrate that a cytokine known to be increased during exacerbation of asthmatic symptoms directly impairs beta-adrenergic function in ASM cells and suggests a mechanism by which inflammation impairs beta-adrenergic receptor signal transduction in asthma.

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