Serine/threonine kinases as molecular targets of antidepressants: implications for pharmacological treatment and pathophysiology of affective disorders
Introduction
Antidepressants are the major therapeutic tools for the treatment of affective disorders, and they are used by a large and increasing proportion of the population in developed countries. However, until recently, the action of these drugs on mood, motivation, and cognition was attributed to their acute effects, their ability to inhibit monoamine neurotransmitter transporters or metabolic enzymes. It was assumed that major depression and dysphoric symptoms arise from a dysfunction of monoamine-based neurotransmission, predominantly serotonin (5-hydroxytryptamine [5-HT] and noradrenaline [NA]), and that blockade of 5-HT/NA transporters or inhibition of monoamine oxidases (MAOs) by increasing the concentrations of extracellular transmitters would re-establish a normal level of neurotransmission Bunney & Davis, 1965, Schildkraut, 1965. This theoretical framework, referred to as the monoamine hypothesis of depression, has been a useful model for drug development for many years, although it does not explain why it takes 2 or more weeks to obtain the therapeutic benefits when the inhibition of uptake occurs in a matter of minutes.
Successive developments neither confirmed nor refuted the hypothesis. If mood was directly related with NA or 5-HT levels, then dietary-induced depletion of NA/5-HT should induce depression. This was never observed in nondepressed healthy individuals. However, NA depletion induced relapse in previously depressed patients successfully treated with NA reuptake inhibitors, but not in those treated with selective 5-HT reuptake inhibitors (SSRIs). The opposite was observed when 5-HT depletion was induced. This confirmed that normal NA or 5-HT synthesis is necessary for the action of antidepressants (Delgado et al., 1994), and suggested that similar therapeutic effects can be attained by targeting different neurotransmitter systems. However, these results also clearly indicated that changes in the availability of monoamine neurotransmitters are not the only factors involved in the action of antidepressants or in the pathophysiology of affective disorders.
Our ability to examine the molecular consequences of antidepressant action allowed a reformulation of the questions in terms of downstream effects of primary drug action on neurotransmitter transporters and receptors. Over the last several years, it has been increasingly appreciated that the delayed effect of antidepressants may be accounted for by adaptive responses in various post-receptor signaling pathways, such as those originating from the large families of G-protein- and tyrosine kinase-coupled receptors Sulser, 1989, Racagni et al., 1992, Hyman & Nestler, 1996, Manji et al., 1996, Duman et al., 1997. This concept is based on a large body of evidence gathered in recent years, and may reconcile several independent observations made at the clinical and preclinical level.
First, adaptive changes in intracellular signaling have a time course compatible with the onset of the therapeutic effect of antidepressants. Several of these adaptations (changes in receptor-coupled G-proteins, in protein phosphorylation, in gene expression) have been shown to occur in a time roughly corresponding to the onset of the antidepressant effect Barden et al., 1995, Nibuya et al., 1995, Popoli et al., 1995, Chen & Rasenick, 1995, Manji et al., 1996, Hyman & Nestler, 1996.
Second, the fact that several signaling pathways may be affected by the drug action is a good explanation for the fact that drugs with different primary mechanisms of action may have similar or equivalent therapeutic actions. Although the stimulation of different receptors may activate different pathways, these pathways may converge downstream, leading to a common neurochemical outcome. Therefore, after the first-generation drugs, such as MAO inhibitors and tricyclic antidepressants, came the SSRIs. More recently, the antidepressant drug armamentarium has been enlarged with inhibitors of both 5-HT and NA reuptake, such as venlafaxine; selective inhibitors of NA reuptake, such as reboxetine; enhancers of NA and 5-HT release, such as mirtazapine (blockers of presynaptic α2-receptors); blockers of 5-HT2 receptors and 5-HT reuptake, such as nefazodone; and other drugs with different mechanisms.
Third, because the action of antidepressants affects multiple signaling pathways, it appears unlikely that the therapeutic outcome of antidepressant treatment is mediated by a single neuronal adaptive modification, such as desensitization of β-adrenoceptors Artigas et al., 1996, Hyman & Nestler, 1996.
The subject of this review is the role of protein kinases and protein phosphorylation in the mechanism of action of antidepressants. Virtually every known signaling pathway impinges at some point on protein kinases or phosphatases. The number of characterized protein kinases is in the vicinity of 1000, and will likely increase in the future. The search for new inhibitors of protein kinases or phosphatases with potential therapeutic function is already an important chapter of biomedical investigation (Graves & Krebs, 1999). A better understanding of the role of protein phosphorylation in neuronal function undoubtedly will contribute to the development of new therapeutic strategies in the treatment of affective disorders.
The covalent, reversible linkage of phosphate to serine, threonine, and tyrosine residues of substrate proteins by multiple protein kinases is probably the most ubiquitous cellular mechanism for regulation of physiological processes Edelman et al., 1987, Graves & Krebs, 1999. Most, if not all, signaling pathways activated by extracellular signals (hormones, neurotransmitters, growth factors, cytokines, etc.) converge on the phosphorylation of downstream protein effectors or additional protein kinases, integrating the signal and propagating it to various cellular compartments. Protein phosphatases catalyze the release of phosphate groups from substrates, thereby providing the basis for a balance between phosphorylation and dephosphorylation that regulates the activity of effector proteins. Most serine/threonine kinases are activated following an increase in cytoplasmic second messengers, such as cyclic AMP (cAMP), Ca2+, and phospholipids. However, the increase in the concentration of a specific second messenger is not the only way by which a subcellular specific response is attained following the arrival of extracellular signals. Activation of protein kinases, phosphatases, and specific substrates in different subcellular compartments occurs through an association of targeting domains of kinases and phosphatases with different targeting loci, often structural proteins that are components of membranes, the cytoskeleton, or cellular organelles Hubbard & Cohen, 1993, Pawson & Scott, 1997. Several anchoring proteins have been identified for different protein kinases Faux & Scott, 1996, Pawson & Scott, 1997.
The three best-characterized serine/threonine multifunctional kinases, protein kinase A (PKA), Ca2+/calmodulin-dependent protein kinase II (CaMKII), Ca2+/phospholipid-dependent protein kinase (PKC), are very enriched in nervous tissue. This has suggested that in addition to regulating general cellular function, they are involved in the control of neural functions, such as receptor and ion channel modulation, neurotransmitter synthesis and release, synaptic strength, and synaptic plasticity. The role of two of these kinases (CaMKII and PKA) in the mechanism of action of antidepressants is addressed here. As for the role of PKC in the action of antidepressants and mood stabilizers, see Lenox et al. (1998) and Manji et al. (1996).
Section snippets
Ca2+/calmodulin-dependent protein kinase II in the brain
CaMKII is a ubiquitous enzyme highly enriched in the brain, where it represents 0.25% of the total protein, accounting for 1% in the cerebral cortex and 2% in the hippocampus (for a review, see Kennedy et al., 1990, Braun & Schulman, 1995, Soderling, 1995). The kinase is present throughout the neuron, associated with postsynaptic densities (PSDs), mitochondria, microtubules, plasma membrane, synaptic vesicles, as well as the cytosolic compartment (Hanson & Schulman, 1992). At the synapses,
Presynaptic protein substrates of Ca2+/calmodulin-dependent protein kinase II: the functional role of synaptotagmin
As illustrated in Section 2.1, CaMKII is involved in the regulation of transmitter release at nerve terminals of most, if not all, neurons. Although the kinase function has only been partly explored at this level, this regulation appears to be carried out by phosphorylation of selected presynaptic protein substrates, including the two predominant substrates of CaMKII in synaptic vesicles: synapsin I and syt. Endogenous phosphorylation of these substrates was increased after long-term
Antidepressant treatment and the cyclic AMP-dependent signaling pathway
A large and growing body of evidence has implicated the cAMP-dependent signaling pathway in the mechanism of action of antidepressants and in the pathophysiology of affective disorders. The pathophysiology is not a subject of this review; for more information, we address the reader to recently published reviews Warsh & Li, 1996, Duman et al., 1997, Perez et al., 2000. First, the general characteristics of cAMP-dependent signaling and protein kinase will be addressed. Second, the modifications
Conclusion
Both clinical and preclinical research investigating the mechanism of action of antidepressant medication in the last several years created the basis for a radical re-examination of the monoamine hypothesis of depression. Thanks to a large body of evidence, it became clear that the therapeutic effect of these drugs is not simply due to their primary actions at the transporter or receptor level, but rather to the delayed adaptive modification of post-receptor signaling pathways. The role of
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