Elucidating biological risk factors in suicide: role of protein kinase A

Abstract

Suicide is a major public health concern. Although there have been several studies of suicidal behavior that focused on the roles of psychosocial and sociocultural factors, these factors are of too little predictive value to be clinically useful. Therefore, research on the biological perspective of suicide has gained a stronghold and appears to provide a promising approach to identify biological risk factors associated with suicidal behavior. Recent studies demonstrate that an alteration in synaptic and structural plasticity is key to affective illnesses and suicide. Signal transduction molecules play an important role in such plastic events. Protein kinase A (PKA) is a crucial enzyme in the adenylyl cyclase signal transduction pathway and is involved in regulating gene transcription, cell survival, and plasticity. In this review, we critically and comprehensively discuss the role of PKA in suicidal behavior. Because stress is an important component of suicide, we also discuss whether stress affects PKA and how this may be associated with suicidal behavior. In addition, we also discuss the functional significance of the findings regarding PKA by describing the role of important PKA substrates (i.e., Rap1, cyclic adenosine monophosphate response element binding protein, and target gene brain-derived neurotrophic factor). These studies suggest the interesting possibility that PKA and related signaling molecules may serve as important neurobiological factors in suicide and may be relevant in target-specific therapeutic interventions for these disorders.

Figure 1

Overview of protein kinase A signaling. In this signaling pathway, the binding of neurotransmitter (NT) to G protein–coupled receptors leads to the activation of G proteins, which, in turn, activate adenylyl cyclase, leading to the production of cyclic adenosine monophosphate (cAMP). In the inactive state, the α subunit of G protein is bound to guanosine diphosphate (GDP) and to βγ subunits. The binding of agonists to receptors causes an interaction of receptors with G proteins, which, in turn, releases GDP in exchange with guanosine triphosphate (GTP). This leads to generation of α-GTP and a βγ subunit dimer. Both α and βγ subunits can interact with effectors. Protein kinase A (PKA) is a holoenzyme composed of two subunits: regulatory (R) and catalytic (C). These regulatory and catalytic subunits form a tetrameric holoenzyme (R₂C₂). In the absence of cAMP, PKA exists as a stable inactive tetramer. The catalytic activity of cAMP is suppressed when the C subunits form a complex with the R subunits. Cyclic AMP, generated in response to adenylyl cyclase activation, binds to the R subunits of tetrameric PKA holoenzymes. The binding of cAMP to an R subunit lowers its affinity for the C subunit. This causes the release of free C subunits. The C subunit can catalyze phosphorylation of substrates in the cytoplasm or, after translocation of the C subunits, in the nucleus. Protein kinase A is also anchored with A kinase–anchoring proteins, causes compartmentalized localization of PKA, and initiates phosphorylation of substrates in a localized fashion. One of the substrates of PKA is transcription factor cAMP response element binding (CREB) protein, which regulates the transcription of many neuronally expressed genes, including brain-derived neurotrophic factor (BDNF). The exchange protein activated by cAMP (Epac) is stimulated by cAMP to exchange GDP with GTP on Rap1. Rap1 can also be regulated by phosphorylation by a C subunit of PKA. Deactivation of PKA is achieved through degradation of cAMP to 5’AMP by cAMP-specific phosphodiesterases (PDEs).

Figure 2

Changes reported in the activation and/or expression of specific catalytic (C) and regulatory (R) subunit isoforms of protein kinase A (PKA), cyclic adenosine monophosphate response element binding protein (CREB), Rap1, and brain-derived neurotrophic factor (BDNF) in suicide brain or during stress. (↓) denotes decrease; and (↑), increase.