Regulation of Signal Transduction Pathways and Gene Expression by Mood Stabilizers and Antidepressants

Regulation of Signal Transduction Pathways and Gene Expression by Mood Stabilizers and Antidepressants

Guang Chen, MD, Khondakar A. Hasanat, MD, Joseph M. Bebchuk, MD, FRCPC, Gregory J. Moore, PhD, Debra Glitz, MD and Husseini K. Manji, MD, FRCPC

From the Department of Psychiatry and Behavioral Neurosciences (G.C., K.A.H., J.M.B., G.J.M., D.G., H.K.M.), Pharmacology (H.K.M.), Radiology (G.J.M.), and Cellular and Clinical Neurobiology Program (G.C., G.J.M., H.K.M.), Wayne State University School of Medicine, Detroit, MI.

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Fig. 1. G protein activation/deactivation cycle. This figure depicts activation of the stimulatory G protein (G_s) by the ßAR receptor, but a similar activation/deactivation cycle is thought to occur with most (if not all) G proteins. The G protein ${alpha}$ subunit cycles between an inactive GDP-bound heterotrimeric ( ${alpha}$ ß ${gamma}$ ) form and an active GTP-bound monomeric form. At rest, an equilibrium exists between the receptor in the high-affinity state (coupled to the G protein) and the low-affinity (uncoupled) state. Activation of receptors by an agonist induces a conformational change in the receptor, allowing it to interact with the G protein, leading to the release of GDP, and the formation of a high-affinity ternary complex (agonist-receptor-G protein). This high-affinity state is short lived, and binding of GTP to the empty nucleotide site on the ${alpha}$ subunit of the G protein leads to a destabilization of the high-affinity complex and a dissociation of the G protein into ${alpha}$ s-GTP and ß ${gamma}$ subunits. It is now well established that both the ${alpha}$ s-GTP and ß ${gamma}$ subunits are able to regulate the activity of various effectors. To date, the best characterized effects of the G protein ß ${gamma}$ subunits are potentiation of the activity of ACs II and IV and activation of certain PLC isozymes, ion channels, and receptor kinases. ${alpha}$ s-GTP is shown to activate ACs in this figure, but there is also evidence demonstrating the direct activation of L-type Ca²⁺ channels by ${alpha}$ s-GTP (at least in certain tissues). The continued activation of effectors by ${alpha}$ -GTP is terminated by the action of a GTPase enzyme intrinsic to the a subunit. The formation of ${alpha}$ s-GDP causes its dissociation from AC; the reassociation of ${alpha}$ s-GDP with ß ${gamma}$ is thermodynamically stable and completes the cycle with the formation of the inactive GDP-bound heterotrimeric ( ${alpha}$ ß ${gamma}$ ) G protein. ATP = adenosine triphosphate; PLC ß = phospholipase C ß isoenzyme; ${alpha}$ _s = ${alpha}$ subunit of stimulatory G protein; ß ${gamma}$ = G protein ß ${gamma}$ subunits.

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Fig. 2. Effects of lithium on the phosphoinositide cycle. In this scheme, occupancy of the receptor (R) by a specific agonist (A) initiates hydrolysis of PIP₂ by PLC. Hydrolysis of PIP₂ by PLC results in the formation of two major second messengers, IP₃ and DAG. IP₃ mobilizes calcium from intracellular stores, whereas DAG activates PKC (see text for details). IP₃ is either dephosphorylated to form inositol 1,4-diphosphate (Ins 1,4,P₂), inositol monophosphate (Ins P₁), and, ultimately, free inositol, or phosphorylated to form inositol 1,3,4,5-tetraphosphate (Ins 1,3,4,5 P₄), which is then dephosphorylated by sequential distinct pathways. Lithium, at therapeutically relevant concentrations, inhibits the dephosphorylation of inositol 1,3,4-triphosphate (Ins 1,3,4 P₃), Ins 1,4,P₂, and all three forms of inositol phosphatases (not shown in detail in the figure). Because the ability of a cell to maintain sufficient supplies of myoinositol is crucial to the resynthesis of the phosphoinositides, and because in most tissues inositol is derived primarily from recycling of inositol phosphates, one early consequence of lithium’s action is to reduce the levels of free inositol. As shown in the figure, inositol depletion can also perturb the DAG limb of the phosphoinositide turnover pathway. Thus, resynthesis of PI involves the transfer of the phosphatidic acidic moiety from cytidine diphosphate DAG to myoinositol. Presumably because of its effect of lowering levels of inositol, lithium treatment of a number of cells has been found to increase the levels of cytidine diphosphate DAG, and its interconvertible metabolite, DAG. Because DAG activates PKC, one consequence of lithium treatment is an activation of PKC. BBB = blood brain barrier.

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Fig. 3. Effects of mood stabilizers on signaling pathways and gene expression. ATP = adenosine triphosphate; CBZ = carbamazepine; G_s = Gi-G proteins mediating stimulation or inhibition of adenylate cyclase; MAPK = mitogen-activated protein kinase; MAPKK = mitogen-activated protein kinase kinase; PKA = protein kinase A; PLC_ß = phospholipase C ß isozyme; R_q = receptors coupled to G protein G_q; R_s = R_i receptors coupled to stimulation or inhibition of AC; RSK = ribosomal S6 kinase; TrK = receptor tyrosine kinase; VPA = valproate.