MinireviewG protein signaling and the molecular basis of antidepressant action
Introduction
Several theories regarding the mechanisms of antidepressant and lithium action have been proposed Manji et al., 1995, Rasenick et al., 1996, Duman et al., 1997, Lenox et al., 1998, Berman and Charney, 1999, Popoli et al., 2001. It is possible that, at the level of the whole brain, elements of the hypothalamic/pituitary/adrenocortical axis are key in the ontogeny of depression and important targets of its therapeutic efficacy Valentino and Curtis, 1991, Owens and Nemeroff, 1999, Holsboer, 2000. Nonetheless, in order to act, antidepressants are likely to have one or more primary molecular targets. Those targets may be at or near the membrane, and altered intracellular signaling (modified neurotransmitter response or responsiveness) is often among the initial effects of antidepressant treatment (Fig. 1). More specifically, the various mechanisms proposed for antidepressant action are consistent with an increase in cAMP production.
Consistent with these theories, it was found that guanylyl-5′-imidodiphoshate [Gpp(NH)p]-or forskolin-stimulated adenylyl cyclase activities were significantly lower in brain membranes of suicide cases with a history of depression than that in control groups (Cowburn et al., 1994). These observations suggested that enhancement of adenylyl cyclase activity induced by antidepressants may be a relevant therapeutic effect. It is possible that the product of the G protein-adenylyl cyclase axis, cAMP, and the myriad proteins phosphorylated by cAMP-dependent protein kinases could be altered by antidepressant treatment. Consistent with the idea of chronic affective drug treatments increasing G protein-effector coupling, is the observation that lithium treatment increased protein kinase C (PKC) activation without altering the amount of PKC, Gq or G11 in rat cerebral cortex (Li et al., 1993). Finally, it has been suggested that immediate early genes and other transcription factors might be activated as a result of chronic antidepressant action (Nibuya et al., 1996). The possibility exists that other gene related changes might occur as well (Hyman and Nestler, 1996).
Antidepressant treatment may alter neurotransmitter function indirectly through the regulation of intracellular signaling. Antidepressant agents may be effective because they modulate converging postsynaptic signals generated in response to multiple endogenous neurotransmitters, including norepinephrine and serotonin. In this context, the signal-transducing G proteins, which play a major role in the amplification and integration of signals in the central nervous system, are in a unique position to affect the functional balance between neurotransmitter systems. There are several possible sites for antidepressant action via G proteins (Fig. 2): 1) the number or affinity of receptors could be altered; 2) the coupling between receptor and G protein could be changed; 3) the number of G proteins could be changed; or the intrinsic properties of a given G protein (e.g. affinity for GTP or rate of GTP hydrolysis) could be modified, 4) the coupling between G proteins and their effectors could be altered or 5) the effectors themselves could be increased in number or intrinsic activity.
Section snippets
β-adrenergic receptors and antidepressant action
In recent years, research has focused on the effects of chronic administration of antidepressants on various aspects of neuronal function. Many of these studies demonstrated alterations in the density and/or sensitivity of several neurotransmitter receptor systems Banerjee et al., 1977, Hertz and Richardson, 1983, Sulser, 1984, Honegger et al., 1986, Okada et al., 1986, Fishman and Finberg, 1987, Fowler and Brannstrom, 1990, Manji et al., 1991, Manji et al., 1992, Duman et al., 1997. In the
Adenylyl cyclase, cAMP and antidepressant action
We first reported that long-term administration of various antidepressants enhanced [Gpp(NH)p]- and fluoride-stimulated adenylyl cyclase activity in rat cortex and hypothalamus membranes (Menkes et al., 1983). This suggested that the stimulatory α-subunit of the G protein, Gs, was a target of antidepressant action and that antidepressant treatment facilitated the activation of adenylyl cyclase by Gs. No change in the intrinsic activity of the adenylyl cyclase occurred subsequent to
G protein expression is not altered by antidepressant treatment
Some groups have suggested that treatments for affective disorder might alter G protein content on the synaptic membrane. This possibility was first raised in a study where GTP binding to brain membranes was performed in rats treated chronically with lithium (Avissar et al., 1988). Changes in isoproteronol-induced GTP binding to membranes were attributed to changes in G protein content in those membranes. Given the multitude of proteins capable of binding GTP (and the likelihood that the moles
Antidepressants, growth factors and nerve growth
It is evident from the above mentioned studies that there is an increase in Gsα/adenylyl cyclase coupling following chronic antidepressant treatment, but events downstream of adenylyl cyclase must be considered in this context as well. Long term increases in cAMP dependent protein kinase activity have been demonstrated in rat cerebral cortex in response to antidepressant treatment Perez et al., 1989, Perez et al., 1991. Consistent with these findings, it has been reported that chronic
Effect of antidepressants on G protein organization of synaptic signaling
G protein signaling complexes at the plasma membrane have been identified as associated with specific components of the membrane and cytoskeleton (Huang et al., 1997). These domains, which contain receptors, G proteins, effector enzymes such as adenylyl cyclase and other membrane associated proteins are likely to be constrained from lateral mobility within the plane of the plasma membrane (Neubig, 1994) in part by cytoskeletal structures which form “corrals” on the inner membrane face (Kuo and
Summary
Despite several decades of research, the molecular basis of depressive disorders and the mechanisms whereby antidepressant drugs alleviate some of the symptoms of those disorders is unknown. Several theories are extant, and most of them are bolstered by some scientific evidence. Nonetheless, decades of research have not allowed us to understand the biological basis of depression. The cellular mechanisms of action of many antidepressants are still unknown and many depressed patients do not
Acknowledgments
The authors thank Jiang Chen, Hiroki Ozawa and Sadamu Toki whose work contributed to this review. Thanks are also expressed to Brian Layden, Josh Sommovilla and Bindu Shah for critical comments and assistance. The work described herein was supported by NIMH.
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