Book Review

Neuronal Signal Transduction Pathways: Wasteland or the Promised Land?

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Science's STKE  15 Aug 2000:
Vol. 2000, Issue 45, pp. pe1
DOI: 10.1126/stke.2000.45.pe1
Review and commentary on Cerebral Signal Transduction: From First to Fourth Messengers, edited by Maarten E. A. Reith.
The Humana Press, Totowa, NJ, 2000. 440 pp. $125.00


Proteins used in signal transduction pathways are commonly found in different cell types and organs. However, specific proteins whose expression is highly restricted are also utilized for allowing discrete responsiveness to signals that are otherwise ignored by other cells. How the brain uses common and specific signal proteins for communication within and beyond the cerebrum has been an area of intense study. A new book concentrates on the signaling that occurs in the brain under normal and pathological conditions--memory, apoptosis, neurodegeneration, depression, and drug dependence--and is filled with chapters written by experts in neurobiology and neurophysiology. Bryan Roth reviews the book and discusses in detail several chapters that may lead to promising future research.

A tacit assumption of neurobiologists has been that neurons are able to communicate through specialized networks of signal transduction molecules. How this might occur has been difficult to describe precisely because few, if any, signal transduction pathways are unique to neuronal systems. To determine how ubiquitous signal transduction systems [e.g., cyclic adenosine 3´,5´-monophosphate (cAMP)/protein kinase A (PKA), diacylglycerol (DAG)/inositol trisphospate (IP3)/protein kinase C (PKC), mitogen-activated protein kinase (MAP), etc.] are coopted by the nervous system to subserve unique and specialized functions in neuronal communication is the goal of a new collection of essays entitled Cerebral Signal Transduction: From First to Fourth Messengers (M. E. A. Reith, Editor).

An even more daunting task is to uncover the ways in which neuronal signal transduction might be altered in pathological conditions and how understanding these alterations might lead to more effective treatment strategies for neuropsychiatric and neurological disorders. Until quite recently, neuropsychiatric research has left a wasteland of ambiguous results. Rather than summarize the many fine chapters in this book, this review will provide a critical evaluation of two chapters to give the reader some flavor of the book as a whole and to highlight areas of opportunity for future research.

Depression: A neurodegenerative disease?: Studies performed 20 to 30 years ago suggested that the initial action of most clinically effective antidepressants was to elevate levels of the biogenic amines serotonin (5-hydroxytryptamine; 5-HT) and/or norepinephrine (NE). However, although the ingestion of antidepressants like fluoxetine (Prozac), sertraline (Zoloft), or other serotonin-selective reuptake inhibitors (SSRIs) boosted neuronal 5-HT levels immediately after administration, the therapeutic effects were delayed for several days to weeks. Thus, this "lag time" between the onset of therapy and a lessening of depression has become an intensely studied phenomenon.

Studies performed by Fridolin Sulser and others suggested that the time required for adaptive changes in adrenergic and serotonergic receptor activity was responsible for this delay between initiating antidepressant therapy and the therapeutic effect of antidepressants (1). This model of antidepressant action implied that receptor down-regulation was the primary event in the therapeutic actions of antidepressants and predicted that therapies that rapidly induced receptor down-regulation would speed up antidepressant actions.

Indeed, some clinical investigators have demonstrated that rapid induction of adaptive changes in 5-HT receptors, for example, might accelerate antidepressant actions. In these studies, coadministration of pindolol (a β-adrenergic antagonist with 5-HT1A partial agonist actions; see the online database of inhibitory constant (Ki) values of psychoactive drugs at with fluoxetine (or a related antidepressant) has been shown in some, but not all studies, to decrease the lag time for antidepressant actions.

As emphasized by Duman in his chapter, strategies based on directly inducing a blockade and/or down-regulation of adrenergic receptors have been unsuccessful. In fact, the blockade of β-adrenergic receptors, which directly decreases the functional activity of β-adrenergic receptors, actually increases the chances of depression. Similarly, drugs (e.g., rolipram) that increase cAMP production exhibit antidepressant effects. Finally, chronic stress--a condition that potentiates depression--leads to down-regulation of adrenergic and serotonergic receptors. Taken together, these observations have led to a reevaluation of the receptor down-regulation hypothesis of antidepressant drug actions.

Duman proposes an integrated model of depression etiology and treatment based on adaptive changes in discrete molecular entities, which has tremendous heuristic and therapeutic promise. Summarizing a large number of studies by Sopolski and McEwen and colleagues, Duman focuses on common molecular end points of chronic stress as a predisposing factor for clinical depression. Specifically, predictable maladaptive changes in signaling cascades involving 5-HT and/or NE receptors, second messenger pathways (involving cAMP/PKA and IP3/PKC), transcription factors [e.g., cAMP response element binding protein (CREB)], and neurotrophins [e.g., brain-derived neurotrophic factor (BDNF)] and incorrect expression of target genes occur in hippocampal and cortical neurons after chronic stress. Indeed, Duman and others have demonstrated that chronic, unpredictable stress leads to decreased neurogenesis, neurite outgrowth, and increased apoptosis of neurons in vivo. Thus, this model implies a pivotal role for BDNF and its receptors, in addition to other as yet unidentified factors, in the etiology of depression.

Indeed, human studies have demonstrated that chronic depression is associated with neuronal loss. Thus, in vivo studies using magnetic resonance imaging (MRI)-based measurements of hippocampal volume, as well as postmortem studies using precise methods of cell counting, have recently demonstrated cell and volume loss with chronic depression. Taken together, these studies have suggested that depression might be a disease manifested, in part, by stress-induced neurodegeneration.

A direct prediction of this "stress-induced neurodegeneration model" of depression is that antidepressant administration should lead to opposite effects on the signaling cascade linking adrenergic and serotonergic receptors to BDNF and other "fourth messengers." Indeed, as summarized by Duman, recent studies have demonstrated that chronic antidepressant treatment leads to increased levels of BDNF and its receptor (TrkB) and that increases in BDNF-mediated signaling are associated with enhanced neuronal sprouting. Also, quite recent studies by Duman's group demonstrate that chronic antidepressant treatment is associated with increased CREB-mediated gene transcription in vivo (2). Finally, Duman alludes to preliminary studies that suggest (i) that activation of 5-HT1A receptors may lead to enhanced neurogenesis and (ii) that BDNF itself may have direct antidepressant actions in animal models of depression (3). This particular chapter and similar recent reviews published elsewhere (3, 4) open up new vistas for treatment of depression and related disorders based on novel molecular entities and pathways (see Fig. 1).

Fig. 1.

Signaling pathways involved in antidepressant actions. The proposed signaling pathway by which antidepressants induce BNDF-mediated gene transcription is illustrated using molecular models of the various signaling entities. First, antidepressants increase the levels of various neurotransmitters (e.g., NE and/or 5-HT), which then activate G protein coupled receptors (GPCRs). GPCR activation then modulates the activity of various second messenger pathways including adenylate cyclase. Activation of adenylate cyclase leads to the activation of PKA, which then phosphorylates CREB. Phosphorylated CREB can then increase transcription of the BDNF gene. Translated BDNF protein is then released extracellularly to activate TrkB receptors. Activation of the TrkB receptors, presumably, leads a transduced signal culminating in the transcriptional activation of additional genes that promote neurite outgrowth and the growth and maintenance of neurons. Depression and chronic stress lead to diminished activation of GPCRs and, ultimately, diminished BDNF, neurite outgrowth, and neuronal loss. Novel targets for antidepressant actions are colored in yellow.

Other chapters by Lattal and Abel (molecular mechanisms of memory), Cotman and colleagues (neuronal apoptosis and neurodegeneration), Post and colleagues (clinical aspects of depression), and Scearce-Levie and Hen (mice with specific genes knocked out as models of drug abuse vulnerability) are also informative and provocative. In particular, an essay by Sasaki, Dawson, and Dawson on the nitric oxide (NO) signaling pathway in the brain warrants comment.

NO: Friend or foe? As summarized in the chapter by Sasaki et al., NO is a ubiquitous second messenger that mediates a number of essential physiological functions including the relaxation of blood vessels, defense against microbial invaders and tumors, and neurotransmission. Additionally, as many users of Viagra can attest, NO has an essential role in penile erection and sexual response in males. These salutary roles of NO have been recently balanced by studies performed by the Dawsons' group and others that suggest that NO and its associated signaling protein partners may also mediate many of the actions of neurotoxic agents. Additionally, these authors suggest that selective NO synthase (NOS) inhibitors may have a protective effect in neurodegenerative/neurotoxic disorders.

As summarized by Sasaki et al., N-methyl-D-aspartate (NMDA) receptor activation--a key event in excitotoxicity--is associated with an influx of Ca2+ that leads to enhanced production of NO through neuronal NOS (nNOS). Enhanced intracellular Ca2+ leads to increased mitochondrial respiration and an increased production of oxygen free radicals including superoxide anions (O2-). The authors propose, on the basis of many prior findings by themselves and others, that NO combines with O2- to form peroxynitrite (OONO-)--a highly reactive intermediate. Peroxynitrite, they propose, specifically damages mitochondrial superoxide dismutatase (MnSOD), the enzyme involved in breaking down O2-, thus leading to even more highly elevated levels of O2-. This leads to a vicious cycle of ↑ O2- → ↑ OONO- → ↑ O2-.

Peroxynitrite may also damage DNA whose presence is sensed by poly(adenosine diphosphate-ribose) polymerase (PARP), leading to the activation of PARP. Although the ultimate significance of PARP activation is uncertain, the authors propose that one consequence may be to consume "free-energy equivalents of ATP [adenosine triphosphate]" by using nicotinamide adenine dinucleotide (NAD). Sasaki et al. propose that a second consequence of elevated NO induced by excitotoxicity, then, is to deplete cellular energy stores and to induce cell death. Indeed, recent in vivo studies by this group have shown that a PARP inhibitor is neuroprotective in an animal model of Parkinson's disease (5). Additionally, PARP knockout mice appear to be less susceptible to cerebral ischemia (6) and, intriguingly, to streptozocin-induced diabetes (7). Although the precise role for PARP in apoptosis is currently undergoing intensive study and is by no means clear, these studies suggest that drugs targeted at PARP and PARP activation pathways mediated by NO may represent novel therapies for neurodegenerative disorders and for diseases mediated by cytotoxicity in general.

Taken together, then, these two essays suggest that novel treatment strategies for neuropsychiatric disorders may result from a detailed understanding of the intricacies of neuronal signal transduction. Other essays propose that new treatments for Alzheimer's disease and drug addiction may also result from insights gained from a detailed knowledge of neuronal communication at the molecular level. The book Cerebral Signal Transduction: From First to Fourth Messengers serves as a useful introductory guide for investigators at all levels of sophistication to the intricacies of neuronal signal transduction. Key essays, as summarized above, also emphasize how this knowledge may lead to improved therapies for age-old maladies.


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