Current Neuropharmacology, 2011, 9, 715-727 715 cGMP Signaling, Phosphodiesterases and Major Depressive Disorder Gillian W. Reierson1, Shuyu Guo2, Claudio Mastronardi2, Julio Licinio2 and Ma-Li Wong2,* 1University of Miami Miller School of Medicine, Miami, FL, USA; 2Department of Translational Medicine, John Curtin School of Medical Research, Australian National University, Acton, ACT, Australia Abstract: Deficits in neuroplasticity are hypothesized to underlie the pathophysiology of major depressive disorder (MDD): the effectiveness of antidepressants is thought to be related to the normalization of disrupted synaptic trans- mission and neurogenesis. The cyclic adenosine monophosphate (cAMP) signaling cascade has received considerable attention for its role in neuroplasticity and MDD. However components of a closely related pathway, the cyclic guanosine monophosphate (cGMP) have been studied with much lower intensity, even though this signaling transduction cascade is also expressed in the brain and the activity of this pathway has been implicated in learning and memory processes. Cyclic GMP acts as a second messenger; it amplifies signals received at postsynaptic receptors and activates downstream effector molecules resulting in gene expression changes and neuronal responses. Phosphodiesterase (PDE) enzymes degrade cGMP into 5’GMP and therefore they are involved in the regulation of intracellular levels of cGMP. Here we review a growing body of evidence suggesting that the cGMP signaling cascade warrants further investigation for its involvement in MDD and antidepressant action. Keywords: Major Depression, cyclic guanosine monophosphate, neurogenesis, neuroplasticity, phophodiesterases, cyclases, antidepressants, pharmacology. 1. INTRODUCTION has received little attention in the biology of MDD and antidepressant action. The cGMP signaling cascade consists Major depressive disorder (MDD) is a chronic and highly of a number of different elements that can regulate cGMP disabling condition. It is the most common mood disorder: levels and influence downstream cellular responses. Fig. (1) up to 17% of the population suffers from this condition at depicts the presynaptic and postsynaptic elements of the some point during their lifetimes. While antidepressants have cGMP signaling pathway in the central nervous system; been shown to be effective in treating the symptoms of MDD these elements are expressed in the hippocampus, a brain in 60-70% of patients, 30-40% of patients do not respond to region that has been implicated in MDD [8, 9]. Pharma- pharmacotherapy [1, 2]. Furthermore, antidepressants must cotherapy targeting different elements of the cGMP pathway be taken chronically for several weeks before treatment re- is currently available; this class of drugs includes phosphodi- sponse is achieved and it is still unclear what are the mecha- esterase inhibitors, which increase cGMP signaling. In this nisms by which these drugs relieve the clinical symptoms of review, we summarize the evidence that supports the role of MDD. Evidence from clinical and preclinical research accu- cGMP signaling in neuroplasticity and in the pathophysiology mulated in recent years support the concept that aberrant of MDD and antidepressant treatment response, with a neuroplasticity, including functional synaptic plasticity and specific focus on the role of phosphodiesterases (PDEs). structural plasticity, in the hippocampus and prefrontal cortex, might underlie MDD [3, 4]. Intracellular cyclic adenosine 2. cGMP SIGNALING COMPONENTS AND THEIR monophosphate (cAMP) signaling activated by brain-derived DISTRIBUTION IN THE BRAIN neurotrophic factor (BDNF) has been shown to be a pivotal player in neuroplasticity and MDD; moreover, studies 2.1. cGMP Synthesis: pGC and sGC have demonstrated that treatment with antidepressants The synthetic enzyme guanylate/guanylyl cyclase (GC) can alter the expression of components of this signaling converts guanosine triphosphate (GTP) to 3’-5’-cyclic pathway in rodents [5-7]. Unfortunately, earlier findings guanosine monophosphate to produce the second messenger have been inconsistently replicated making it premature to molecule known as cGMP. The production of cGMP by GC conceptualize translational strategies for new antidepressant can occur in two different ways: 1) following activation of pharmacotherapy targeting the cAMP signaling. The cyclic membrane bound guanylate cyclase (particulate GC or pGC) guanosine monophosphate (cGMP) signaling pathway is [10, 11] and 2) following activation of soluble guanylate an intracellular nucleotide cascade that is also involved in cyclase (sGC, also called NO receptors) in the cytoplasm by neuroplasticity. It is closely related to cAMP signaling, but it the diffusible second messenger molecule, nitric oxide (NO) [12, 13]. *Address correspondence to this author at Building 131, Garran Road, John Curtin School of Medical Research, The Australian National University Particulate GC is composed of two subfamilies: the pep- Canberra, ACT, Australia; Tel: +61 2 6125 8557; Fax: +61 2 6125 2337; tide hormone receptor subfamily, which binds natriuretic 2+ E-mail: [email protected] peptides, and the Ca -modulated ROS-GC (rod outer 1570-159X/11 $58.00+.00 ©2011 Bentham Science Publishers 716 Current Neuropharmacology, 2011, Vol. 9, No. 4 Reierson et al. cAMP PDE sGC cGMP PKGI VASP Glutamate CNG CNG AMPA receptor insertion Synaptic protein NO Neurogensis accumulation AMPAR AMPAR NMDAR NMDAR AMPAR AMPAR PI3K/Akt/Gsk3 Ca2+ CaMK L-Arginine nNOs L-Citrulline NO O2 PKGII sGC cGMP PKGI VASP PKG Transcription apparatus CREB Genetic Changes Nucleus Fig. (1). The cGMP signaling pathway. Presynaptic (top) and postsynaptic (bottom) elements of the cGMP signaling cascade are represented. AMPAR = 2-amino-3-(5-methyl-3-oxo-1,2-oxal-4-yl)propanoic acid receptor; CaMK = calcium-calmodium-dependent kinase; cAMP = cyclic adenosine monophosphate; cGMP = cyclic guanosine monophosphate; CNG = cyclic nucleotide gated channels; NO = nitric oxide; nNO = neuronal NO; PDE = phosphodiesterase; PI3K/AKT/Gsk3 = phosphoinositide 3-kinase/protein kinase B (aka AKT)/glycogen synthase kinase 3; PKGI = cGMP dependent protein kinase I; PKGII = cGMP dependent protein kinase II; sGC = soluble guanylate cyclase; VASP = vasodilator-stimulated phosphoprotein. cGMP Signaling, Phosphodiesterases and Major Depression Disorder Current Neuropharmacology, 2011, Vol. 9, No. 4 717 segment-derived guanylate cyclase) subfamily, which is PDE9) and dual substrate PDEs (PDE1, PDE2, PDE3, linked with the senses of vision, olfaction and taste, and PDE10, and PDE11). light-regulated pinealocytes [1, 14-16]. The isoforms of pGC All cGMP specific PDEs are expressed in the brain. In expressed in the brain include guanylate cyclase A/natriuretic peptide receptor 1 (GC-A/Npr1), guanylate cyclase B/natriuretic the rodent brain, PDE5A mRNA expression has been re- ported in the purkinje cells of the cerebellum; strong staining peptide receptor 2 (GC-B/Npr2), guanylate cyclase 2D (GC- has also been observed in scattered cells in the hippocampus, D/GUCY2D); while two eye-specific GC have been identi- including pyramidal cells of CA1, CA2 and CA3, as well as fied in mammals (designed GC-E and GC-F or RetGC-1 and in the dentate gyrus [33]. PDE6 was initially thought to be RetGC-2 in humans) [17-19]. GC-A/Npr1 is activated by limited to the retina; however, PDE6B mRNA expression atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) and the mRNA is expressed in the subfornical organ, has also been reported in mouse hippocampus [34]. CNS expression of the PDE9A mRNA in the rodent brain has medial habenula, cerebellum and olfactory bulb [20, 21]. been reported in the purkinje cells and granule cells of the GC-B/Npr2 is activated by natriuretic peptide type C (CNP) cerebellum, olfactory bulb and tubercle, caudate putamen, and the mRNA is expressed in the pineal gland, cerebellum, and CA1 and dentate gyrus areas of the hippocampus [35- cortex, hippocampus, hypothalamus, olfactory bulb, neural 37]. In the human brain, PDE9 mRNA expression has been lobe of the pituitary gland, and thalamus [21, 22]. GC-D is expressed in the olfactory bulb in rodents, but it is a reported in the insular and visual cortices as well as in the CA1, CA2 and CA3 subfields, and dentate gyrus of the hip- pseudogene in humans [23]. pocampal formation [38]. Soluble GC exists as a heterodimer composed of differ- All dual substrate cGMP are also expressed in the brain. ent combinations of subunits (1 or 2) and subunits In rodents, in situ hybridization and immunohistochemistry (1 or 2); all sGC subunits mRNAs are expressed in the studies demonstrated that the PDE1A isoform is expressed in brain with the exception of the 2 subunit mRNAs [24]. the following brain areas: cerebral cortex, pyramidal cells of Both 1 and 2 sGC subunits mRNAs are expressed in the the hippocampus, and striatum [39, 40]. PDE1B is also ex- cerebral cortex and olfactory bulb; 1 is also expressed in pressed in several brain areas including the caudate-putamen, striatum and pallidum and 2 is also expressed in hippocam- nucleus accumbens, dentate gyrus of hippocampus, olfactory pus and medulla [21]. The 1 sGC subunit mRNA is tubercle, medial thalamic nuclei, and brainstem [39, 40]. expressed throughout the brain, with predominant expression PDE1C mRNA is expressed in the granule cells of the cere- in the cerebral cortex, hippocampus, lateral septal complex, olfactory bulb, and striatum [21, 24]. In the