Beyond receptors: Multiple second‐messenger systems in brain

ABSTRACT. Cerebral hypoxia-ischemia remains a major cause of acute perinatal brain injury, leading ultimately to neurologic dysfunction manifest as cerebral palsy, mental retardation, and epilepsy. Research in experimental animals over the past 10 or more years has expanded greatly our understanding of the cellular and molecular events that occur during a hypoxic-ischemic insult to brain, and recent discoveries have suggested that metabolic pertubations arising in the recovery period after resuscitation contribute substantially to the nature and extent of neuronal destruction. The review focuses on those neurochemical processes responsible for the maintenance of cellular homeostasis and how these mechanisms fail in hypoxia-ischemia to culminate in brain damage. Knowledge of these critical events has opened new avenues of potential therapy for the fetus and newborn infant subjected to cerebral hypoxiaischemia to prevent the serious delayed effects of perinatal brain injury. Perinatal cerebral hypoxia-ischemia typically is initiated by compromised placental or pulmonary gas exchange which leads to systemic hypoxia/anoxia with or without concurrent hypercapnia (asphyxia) (1). Hypoxia/hypercapnia increases CBF adequate to maintain brain metabolism stable until cerebral ischemia supervenes owing to cardiac depression with secondary bradycardia and systemic hypotension. With the neuronal oxygen and glucose debt arising from ischemia, oxidative metaboReceived August 16, 1989; accepted November 30, 1989. Supported by Grants HD-09 109, HD-15738, HD-199 13, and HL-19190 from the NIH and by grants from the American Heart Association and American Diabetes Association. lism shifts to anaerobic glycolysis with its inefficient generation of high-energy phosphate reserves necessary to maintain cellular ionic gradients and other metabolic processes. Ultimately, cellular energy failure occurs, which, if not promptly reversed, results in death of the cell.Over the past decade, a wealth of research has expanded our knowledge of those critical cellular metabolic events that eventually lead to tissue injury arising from hypoxia-ischemia. Investigations have shown that hypoxia-ischemia sets in motion a cascade of biochemical alterations that are initiated during the course of the insult and that proceed well into the recovery period after resuscitation. This review will highlight those cellular processes involved in this metabolic cascade and how they evolve into perinatal hypoxic-ischemic brain damage. CELLULAR ENERGY TRANSFORMATIONSATP is the primary energy modulator of the cell (2-4). Its two -P exist at an energy level capable of providing the necessary driving force for innumerable biochemical reactions and physiologic processes. ATP not only promotes energy consuming reactions but also drives physiologic processes (e.g. ion pumping) by acid hydrolysis. As such, the compound provides the cellular free energy necessary to maintain neuronal viability with its specialized function.Under physiologic conditions, cellular ATP is maint...

show abstract

“…Courtesy of S. J. Vannucci. (85,86). According to currently accepted concepts, neurotransmitter (e.g.…”

Section: Y~o S O~mentioning

confidence: 99%

Experimental Biology of Cerebral Hypoxia-Ischemia: Relation to Perinatal Brain Damage

1990

View full text Add to dashboard Cite

show abstract

“…Insight into the function of a number of brain proteins has been derived from mapping their regional localizations (17). To clarify the role of c-src in mammalian brain, we have localized its mRNA by in situ hybridization.…”

Section: Introductionmentioning

confidence: 99%

“…This brain-specific form has been termed c-src+ (13); we refer to the form without the insert as c-src-. The functional significance of this insert, as well as of c-src expression in general, in brain is little understood.Insight into the function of a number of brain proteins has been derived from mapping their regional localizations (17). To clarify the role of c-src in mammalian brain, we have localized its mRNA by in situ hybridization.…”

mentioning

confidence: 99%

Brain-specific src oncogene mRNA mapped in rat brain by in situ hybridization.

Ross

Wright

Resh

et al. 1988

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Brain src protooncogene is expressed in two forms, one identical to message in other tissues, and one containing an 18-nucleotide insert specific to brain. We have mapped mRNA for the two forms of src in rat brain with selective antisense oligonucleotide probes to the brain (src+) and peripheral (src-) forms. Fetal rat src mRNA levels were much higher in the central nervous system than any peripheral organ. In adult brain, src+ mRNA level was highest in the internal granular layer of the olfactory bulb, pyramidal cells of the hippocampus, granule cells of the dentate gyrus, and cerebellar granule cells. src+ and src-levels were similar in hindbrain, but src+ levels were higher than those of src-in forebrain. These distributions suggest that src+ may play roles in a number of neural processes, possibly including neuronal plasticity.While viral oncogenes were originally identified because of their ability to cause transformation of cells, they are now known to be closely related to cellular oncogenes, which are expressed in normal tissues (1). Several oncogenes are most highly expressed in mammalian brain (2)-the one adult tissue in which the major cellular constituent (the neuron) never divides. c-src, one of the best studied oncogenes, encodes a tyrosine kinase located on the inner surface of the cell membrane (2). The c-src oncogene probably does not induce proliferation in vivo, but rather may be involved in control of differentiation and cell to cell communication (3,4). c-src is expressed at high levels in both fetal and adult brain (5-12). Brain c-src message is expressed in two forms, one identical to c-src in other tissues, and an additional form not present in other tissues, containing an 18-nucleotide insert between exons 3 and 4, which may alter c-src protein (ppc60src) phosphorylation (13-16). This brain-specific form has been termed c-src+ (13); we refer to the form without the insert as c-src-. The functional significance of this insert, as well as of c-src expression in general, in brain is little understood.Insight into the function of a number of brain proteins has been derived from mapping their regional localizations (17). To clarify the role of c-src in mammalian brain, we have localized its mRNA by in situ hybridization. We report a neuronal localization of both c-src+ and c-src-mRNA and describe regional variations in expression with implications for function. MATERIALS AND METHODSRats (175-250 g, male Sprague-Dawley) were anesthetized with sodium pentobarbital and perfused via the left cardiac ventricle with 50-100 ml of 15% sucrose in 50 mM sodium phosphate buffer (pH 7.4). Brains were rapidly removed, embedded in brain paste, and frozen on dry ice. Sections (12 ,um thick) were cut in a cryostat onto slides coated with gelatin/chrome alum, and stored at -70'C. In situ hybridization was done by methods previously described with minor modifications (18)(19)(20). Solutions were made with deionized distilled water treated with 0.1% diethylpyrocarbamate and autoclaved. Sections were fix...

show abstract

“…Despite a general acceptance of the overall sequence of events responsible for linking receptor activation to increases of cytosolic free Ca2" (10)(11)(12)(13), many details of the mechanisms underlying each step remain unresolved. Recent advances suggest a high level of cellular diversification and the presence of an intricate network of positive and negative controls providing continuous regulation of the response elicited by receptor activation.…”

Section: Introductionmentioning

confidence: 99%

Signal Transduction Mechanisms Involved in Hormonal Ca 2+ Fluxes

Williamson¹,

Monck²

1990

Environmental Health Perspectives

View full text Add to dashboard Cite

This article reviews literature up to mid-1988 covering recent developments pertaining to agonist-induced Ca2`signaling in various cell types. A large amount of experimental evidence supports a mechanism involving specific guanine nucleotide-binding proteins (G-proteins) as transducing factors between occupancy of a wide variety of receptors by many different agonists and activation of polyphosphoinositide specific phospholipase C enzymes. Although many different G-proteins and phospholipase C enzymes have been purified and cloned, successful reconstitution of the components has not been achieved. Hence, many questions concerning the specificity of coupling between particular receptors to a particular G-protein and phospholipase C subtype remain unresolved. Phospholipase C subtypes isolated from the membrane and soluble fractions of the cell are directly activated by Ca2" and, preferentially, hydrolyse phosphatidylinositol 4,5-bisphosphate (PIP2) and phosphatidylinositol 4-phosphate (PIP). The role of the G-protein is to stimulate inositol lipid breakdown at free Ca2' concentrations (0.1-0.2 FM) typical of unstimulated cells. Overwhelming evidence supports the concept that Ins 1,4,5-P3, the product of PIP2 hydrolysis, is responsible for the initial agonist-induced Ca2' transient by mobilization of Ca2+ from a specialized intracellular store. An Ins 1,4,5-P3 receptor has been purified that may correspond to the postulated Ins 1,4,5-P8 gated Ca21 channel. Despite a growing understanding of the complexities of the metabolism of Ins 1,4,5-P8 and a successful purification of many enzymes involved, including the ATP-dependent 3-kinase that converts Ins 1,4,5-P8 to Ins 1,3,4,5-P4, the role of Ins 1,3,4,5-P4 as a putative second messenger remains enigmatic. Multiple forms of protein kinase C have been described and the role is well established for a 1,2-diacylglycerol, the second product of PIP2 hydrolysis, as its physiological activator. Although protein kinase C has been shown to phosphorylate and modulate the activity of several proteins involved in the Ca2' signaling pathway and Ca2+ transport, the physiological significance of the protein kinase C in agoniststimulated cell function requires further elucidation. The extension of measurements of hormoneinduced Ca2+ changes to single cells has shown that the occurrence of Ca2+ oscillations is a common phenomena. Elucidation of the biochemical mechanisms causing this oscillatory response and its physiological significance represents an important challenge for future studies. IntroductionThe cytosolic free Ca2" concentration functions as an important intracellular signaling mechanism whereby hormones and growth factors regulate many different cellular processes such as secretion, metabolism, neurotransmitter release, cell growth, and differentiation. Signal transduction by the ligandactivated receptor is mediated by specific guanine nucleotide binding proteins (G-proteins), which activate phospholipase C-mediated hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP...

show abstract

Beyond receptors: Multiple second‐messenger systems in brain

Cited by 108 publications

References 127 publications

Experimental Biology of Cerebral Hypoxia-Ischemia: Relation to Perinatal Brain Damage

Experimental Biology of Cerebral Hypoxia-Ischemia: Relation to Perinatal Brain Damage

Brain-specific src oncogene mRNA mapped in rat brain by in situ hybridization.

Signal Transduction Mechanisms Involved in Hormonal Ca 2+ Fluxes

Contact Info

Product

Resources

About