top of page

Monday Article #55: The Role of Protein Kinase A in Anxiety Behaviors

Anxiety, experienced as excessive, uncontrollable worry about a variety of topics In the absence of respective stimuli or in a manner disproportionate to their potentially posed risk, is the key diagnostic criterion of generalized anxiety disorder (GAD). [1] Its etiological interrelatedness with dimensional measures of trait anxiety, such as pathological worry, fear of uncertainty, or neuroticism, and its high rate of treatment resistance have attracted the attention of psychiatric geneticists aiming at identifying biomarkers of disease risk and treatment response. [2]

Some people may experience clinically significant anxiety symptoms. This can manifest as anxiety in specific, non-threatening situations, panic symptoms, or generalized feelings of worry that occur most or all of the time. When anxiety symptoms cause distress or impairment, they are considered clinically significant and may result in a diagnosis of an anxiety disorder. [3]

Figure 1. An illustration of anxiety disorder.

Available data suggest that fear-related disorders are highly complex and polygenic, and despite substantial progress in genetics (and epigenetics), few responsible loci have been identified for these disorders. Recently, molecular genetic approaches, including genomic studies, have been applied to identify pathways that are associated with anxiety risk. There is now ample experimental and preclinical evidence showing that anxiety disorders are associated with abnormal neural processing of threat-related stimuli, which is mediated by the cyclic AMP (cAMP)-protein kinase A (PKA) pathway. In addition, stress in sensitive phases of development may influence structural integrity of specific brain regions and neural processing pathways involved in emotion regulation, consistent with a gene-environment-timing interaction in mood dysregulation. [4]

PKA Pathway

PKA is an evolutionarily conserved serine threonine kinase that regulates diverse signal transduction pathways, including cellular development, proliferation, differentiation, apoptosis, and tumorigenesis. PKA is considered the main target for cAMP in the cell, is widely distributed and serves as the principal effector mechanism for G-coupled receptors linked to adenylate cyclase [5]. In the absence of cAMP, PKA is an inactive tetrameric holoenzyme consisting of two catalytic (C) subunits bound to a regulatory (R) subunit dimer, which is compartmentalized to distinct locations in the cell by A-kinase anchoring proteins (AKAPs) [6]. AKAPs contribute to maintaining specificity of PKA signaling, but it is also believed that several isoforms and splice variants of especially the C subunits are important mediators of specificity.

Based on the elution profile on diethylaminoethyl cellulose exchange chromatography, two isoforms of the PKA heterotetrameric enzyme, PKA-I and -II, exist in most cells. The different PKA subtypes (types I and II) have different affinity for cAMP. This is due to the presence of either type I or II R subunits. There are four such subunits in humans (and mice): RIα and RIβ, and RIIα and RIIβ, coded by the PRKAR1A, PRKAR1β, PRKAR2A, and PRKAR2β genes, respectively [7].

R subunits form a homodimer that binds two C subunits (one each); there are four C subunits in humans (and mice): Cα, Cβ, Cγ, and protein kinase X gene (PRKX), coded by the PRKACA, PRKACB, PRKACG, and PRKX genes, respectively, in the PKA tetramer (R2C2). When the R and C subunits form a complex, the cAMP-catalytic activity is suppressed. As shown in knockout (KO) mouse studies, these four genes function in a tissue and cell type-specific manner to regulate accurately the activity of the C subunits [8].

Figure 2. The PKA enzyme is central in the regulation of the cAMP-signalling pathway.

The Role of PKA in Anxiety

PKA activity is affected by various neurotransmitters (i.e. acetylcholine, dopamine, norepinephrine, serotonin, and histamine) that are involved in alertness, anxiety, emotion, or mood indirectly through the stimulation of the G-protein-coupled receptor or adenyl cyclase or directly by cAMP [9]. The CRE is present in many genes and functions as a promoter/enhancer element in many brain areas that respond to environmental stimuli [10]. The observed differences in memory processes that are associated with mood, anxiety, or emotion are likely due to the effects of substances that affect adenyl cyclase activity. For example, dopaminergic D1 and B-noradrenergic receptors enhance, while serotonin receptors inhibit the activity of adenyl cyclase [11].

Signaling activity in neural circuits before or after stimuli may influence PKA activity and long-term potentiation (LTP), affecting fear learning and memory of the event [12]. PKA has two peaks of activity in the process of long-term memory formation, with the first occurring a few minutes after the event, and the second occurring 2-3 h after the event (requires both transcription and protein synthesis). The PKA pathway is also an important component of short-term memory within the first hour after the event. The phosphorylated form of CREB also increases at these same time periods as PKA and contributes to the synthesis of new proteins that are essential for long-term memory formation [11].

Inhibitors of Protein Synthesis or PKA activity

Research with transgenic mouse models with inhibitors of protein synthesis or PKA activity demonstrate that inhibition of PKA activity blocks LTP in the hippocampus and interferes with memory consolidation for fear in the amygdala [13] Infusion of PKA inhibitors into BLA immediately following fear-conditioning training dose-dependently blocked consolidation of fear memory (24 h after training) but not short-term memory(4 h) [14]. Infusion of inhibitor Rp-cAMPs into the CEA decreased CREB function and decreased neuropeptide Y (NPY) expression and provoked anxiety-like behavior and alcohol intake in nonpreferring rats [15].

Table 1: Preclinical research studies of anxiety or fear memory using stimulation, direct or indirect inhibition of PKA pathway, protein synthesis and various transgenic mice model

PKA-Related Targets Associated with Anxiety-Like Behaviors

Evidence from preclinical studies demonstrate that various targets in the PKA pathway are involved in the regulation of emotional behavior and alterations in this pathway are associated with anxiety and other comorbid behaviors and are therapeutic targets. For example, mice with targeted ablation of CREB during adulthood in forebrain neurons showed severe anxiety phenotype but unaltered hippocampal-dependent long-term memory in context-dependent fear conditioning. CREB protein during adulthood seems to be pivotal for the regulation of emotional behavior [16]. Other PKA-related neural receptors involved in anxiety-like behavior include the glutamate receptor GLuR1 [17] calmodulin signaling [18] corticotropin-releasing factor (CRF)-1 receptors within medial PFC [19], and cAMP-regulated phosphoprotein 32 kDa [20].


  1. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Arlington. (2013 ). American Psychiatric Association .

  2. Borwin Bandelow, Sophie Michaelis . (2015 , September 17 ). Epidemilogy of anxiety disorders in the 21st Century . Retrieved from National Library of Medicine:

  3. Michael G. Gottshalk, Katharina Domschke . (2017 , June 19 ). Genetics of generalized anxiety disorder and related traits. Retrieved from National Library of Medicine :

  4. Gil Zalsman, Avihany Gutman, Liat Shbiro, Ruth Rosenan, J. John Mann, Aron Weller . (2015 , November). Genetic vulnerability, timing of short-term stress and mood regulation: A rodent diffusion tensor imaging study. Retrieved from ScienceDirect :

  5. Skalhegg BS, Tasken K. (2000, August 1). Specificity in the cAMP/PKA signaling pathway. Differential expression, regulation, and subcellular localization of subunits of PKA. Retrieved from NLM:

  6. Doskeland SO, Maronde E, Gjertsen BT. (1993 , September 13). The genetic subtypes of cAMP-dependent protein kinase - functionally different or redundant? Retrieved from NLM:

  7. Nesterova M, Bossis I, Wen F, Horvath A, Matyakhina L, Stratakis CA. (2008, February ). An immortalized human cell line bearing a PRKAR1A-inactivating mutation: effects of overexpression of the wild-type allele and other protein kinase A subunits. Retrieved from NLM :

  8. Amieux PS, McKnight GS. (2002, June). The essential role of RI alpha in the maintenance of regulated PKA activity. Retrieved from NLM:

  9. Arnsten AF, Ramos BP, Birnbaum SG, Taylor JR:. (2005). Protein kinase A as a therapeutic target for memory disorders: rationale and challenges. Retrieved from NLM:

  10. Konradi C, Cole RL, Heckers S, Hyman SE. (1994 ). Amphetamine regulates gene expression in rat striatum via transcription factor CREB. Retrieved from NLM:

  11. Vianna MR, Coitinho AS, Izquierdo I. (2004 ). Role of the hippocampus and amygdala in the extinction of fear-motivated learning. Retrieved from NLM :

  12. Abel T, Nguyen PV, Barad M, Deuel TA, Kandel ER, Bourtchouladze R. (1997 ). Genetic demonstration of a role for PKA in the late phase of LTP and in hippocampus-based long-term memory. Retrieved from ScienceDirect :

  13. Matthies H, Reymann KG. (1993). Protein kinase A inhibitors prevent the maintenance of hippocampal long-term potentiation. Retrieved from NLM:

  14. Schafe GE, Atkins CM, Swank MW, Bauer EP, Sweatt JD, LeDoux JE. (2002). Activation of ERK/MAP kinase in the amygdala is required for memory consolidation of pavlovian fear conditioning. . Retrieved from NLM:

  15. Pandey SC, Zhang H, Roy A, Xu T. (2005 ). Deficits in amygdaloid cAMP-responsive element-binding protein signaling play a role in genetic predisposition to anxiety and alcoholism. Retrieved from JCI :

  16. Barrot M, Olivier JD, Perrotti LI, DiLeone RJ, Berton O, Eisch AJ, et al. (2002). CREB activity in the nucleus accumbens shell controls gating of behavioral responses to emotional stimuli. Retrieved from NLM:

  17. Svenningsson P, Arts J, Gunne L, Andren PE. (2002). Acute and repeated treatment with l-DOPA increase c-jun expression in the 6-hydroxydopamine-lesioned forebrain of rats and common marmosets. Retrieved from NLM:

  18. Davis MM, Olausson P, Greengard P, Taylor JR, Nairn AC. (2012). Regulator of calmodulin signaling knockout mice display anxiety-like behavior and motivational deficits. Retrieved from Wiley Online Library :

  19. Miguel TT, Gomes KS, Nunes-de-Souza RL. (2014 ). Tonic modulation of anxiety-like behavior by corticotropin-releasing factor (CRF) type 1 receptor (CRF1) within the medial prefrontal cortex (mPFC) in male mice: role of protein kinase A (PKA). Retrieved from ScienceDirect:

  20. Heyser CJ, Fienberg AA, Greengard P, Gold LH. (2000). DARPP-32 knockout mice exhibit impaired reversal learning in a discriminated operant task. Retrieved from ScieneDirect :

Stay Up-To-Date with New Posts

Search By Tags

bottom of page