A Potential Role for a Genetic Variation of AKAP5 in Human Aggression and Anger Control

Abstract

The A-kinase-anchoring protein 5 (AKAP5), a post-synaptic multi-adaptor molecule that binds G-protein-coupled receptors and intracellular signaling molecules has been implicated in emotional processing in rodents, but its role in human emotion and behavior is up to now still not quite clear. Here, we report an association of individual differences in aggressive behavior and anger expression with a functional genetic polymorphism (Pro100Leu) in the human AKAP5 gene. Among a cohort of 527 young, healthy individuals, carriers of the less common Leu allele (15.6% allele frequency) scored significantly lower in the physical aggression domain of the Buss and Perry Aggression Questionnaire and higher in the anger control dimension of the state-trait anger expression inventory. In a functional magnetic resonance imaging experiment we could further demonstrate that AKAP5 Pro100Leu modulates the interaction of negative emotional processing and executive functions. In order to investigate implicit processes of anger control, we used the well-known flanker task to evoke processes of action monitoring and error processing and added task-irrelevant neutral or angry faces in the background of the flanker stimuli. In line with our predictions, Leu carriers showed increased activation of the anterior cingulate cortex (ACC) during emotional interference, which in turn predicted shorter reaction times and might be related to stronger control of emotional interference. Conversely, Pro homozygotes exhibited increased orbitofrontal cortex (OFC) activation during emotional interference, with no behavioral advantage. Immunohistochemistry revealed AKAP5 expression in post mortem human ACC and OFC. Our results suggest that AKAP5 Pro100Leu contributes to individual differences in human aggression and anger control. Further research is warranted to explore the detailed role of AKAP5 and its gene product in human emotion processing.

Local cAMP signaling in disease at a glance

“…The incidence and economic burden of these disorders is set to increase as average global lifespans rise. Further diseases that impinge on the area of perturbed local cAMP signaling include obesity (Cummings et al, 1996;Czyzyk et al, 2008), asthma (Gerthoffer et al, 2013), and neurodegenerative and behavioral disorders (Bernstein et al, 2013;Millar et al, 2005;Reissner, 2013;Renthal et al, 2009;Richter et al, 2011). There is a growing awareness among structural biologists and pharmacologists that the higherorder topology of signaling protein complexes should be considered when contemplating therapeutic intervention (Blundell et al, 2011).…”

Effects of AKAP5 Pro100Leu Genotype on Working Memory for Emotional Stimuli

“…Genotyping was performed on DNA extracted from blood leukocytes using PCR-based allele-specific restriction analysis [39]. Briefly, the DNA fragment containing the AKAP5 Pro100Leu polymorphism (Chr 14q21-24) was amplified using the primers AKAP5_100-f (5'-GCT TCT GAT CAG CCA GAG CCC AC-3') and AKAP5_100-r (5'-GCT TCT TCC TGG ACT TTG ATG CTG CAG-3') and standard Taq polymerase (Qiagen and Fermentas).…”

“…We could recently demonstrate that, in healthy young human participants, a functional genetic polymorphism of the AKAP5 gene, Pro100Leu (NCBI accession #: rs2230491), affects anger control and physical aggressive behavior. Carriers of the less common Leu allele show lower physical aggression and higher anger control [39]. On the neural level, Leu carriers showed a more effective dACC-mediated control of emotional interference in a modified flanker task with emotional distracters (faces) when compared to Pro homozygotes.…”

“…In the original EFNBACK task, target faces were flanked by emotional or neutral distracters. These were omitted in a simplified EFNBACK task used in the present study in order to avoid interfering effects previously observed in a flanker task with emotional distracters [39]. We hypothesized that, because of their presumably higher emotional reactivity, Pro homozygous subjects might show an advantage in the encoding and maintenance of emotional faces and hence perform the working memory task more successfully.…”

Social neuroscience: the second phase

“…Richter et al (2011) demonstrate that a polymorphism in AKAP5 is associated with both explicit reports of aggressive behavior, anger expression and anger control, and implicit regulation of anger. These differences manifested at the neural level as well, implicating enhanced activation in ACC during the processing of angry faces among individuals with the polymorphism associated with decreased aggression.…”