Conformational changes in protein kinase A along its activation cycle are rooted in the folding energetics of cyclic-nucleotide binding domains.

Cyclic-nucleotide binding (CNB) domains are structurally and evolutionarily conserved signaling modules that regulate proteins with diverse folds and functions. Despite a wealth of structural information, the mechanisms by which CNB domains couple cyclic-nucleotide binding to conformational changes involved in signal transduction remain unknown. Here we combined single-molecule and computational approaches to investigate the conformation and folding energetics of the two CNB domains of the regulatory subunit of protein kinase A (PKA). We found that the CNB domains exhibit different conformational and folding signatures in the apo state, when bound to cAMP, or when bound to the PKA catalytic subunit, underscoring their ability to adapt to different binding partners. Moreover, we show while the two CNB domains have near-identical structures, their thermodynamic coupling signatures are divergent, leading to distinct cAMP responses and differential mutational effects. Specifically, we demonstrate mutation W260A exerts local and allosteric effects that impact multiple steps of the PKA activation cycle. Taken together, these results highlight the complex interplay between folding energetics, conformational dynamics, and thermodynamic signatures that underlies structurally conserved signaling modules in response to ligand binding and mutational effects.

PTSD Symptoms, Emotion Dysregulation, and Alcohol-Related Consequences Among College Students With a Trauma History.

OBJECTIVE: Posttraumatic stress disorder (PTSD), alcohol use, and alcohol-related consequences have been linked to emotion dysregulation. Sex differences exist in both emotion regulation dimensions and alcohol use patterns. This investigation examined facets of emotion dysregulation as potential mediators of the relationship between PTSD symptoms and alcohol-related consequences and whether differences may exist across sexes. METHODS: Participants were 240 college students with a trauma history who reported using alcohol within the past three months and completed measures of PTSD symptoms, emotion dysregulation, alcohol consumption, alcohol-related consequences, and negative affect. The six facets of emotion dysregulation were examined as mediators of the relationship between PTSD symptoms and alcohol-related consequences in the full sample and by sex. RESULTS: There were differences in sexes on several variables, with women reporting higher PTSD scores and lack of emotional awareness. Men reported significantly more drinks per week in a typical week and a heavy week. There were significant associations between the variables for the full sample, with PTSD showing associations with five facets of emotion dysregulation subscales: impulse control difficulties when upset, difficulties engaging in goal-directed behavior, nonacceptance of emotional responses, lack of emotional clarity, and limited access to emotion regulation strategies. Alcohol-related consequences were associated with four aspects of emotion dysregulation: impulse control difficulties when upset, difficulties engaging in goal-directed behavior, nonacceptance of emotional responses, and limited access to emotion regulation strategies. Two aspects of emotion regulation, impulse control difficulties and difficulties engaging in goal directed behavior, mediated the relationship between PTSD symptoms and alcohol-related consequences in the full sample, even after adjusting for the effects of negative affect. When examined separately by gender, impulse control difficulties remained a mediator for men and difficulties engaging in goal directed behavior for women. CONCLUSIONS: These analyses shed light on processes that may underlie "self-medication" of PTSD symptoms. Gender-specific interventions targeting emotion dysregulation may be effective in reducing alcohol-related consequences in individuals with PTSD. Women may possibly benefit from interventions that focus on difficulties engaging in goal-directed behavior, while men may benefit from interventions that target impulse control difficulties when upset.

Drinking motives among heavy-drinking veterans with and without posttraumatic stress disorder.

OBJECTIVE: This study examined patterns of drinking motives endorsed by heavy drinking veterans who either did or did not meet criteria for posttraumatic stress disorder (PTSD). METHOD: Data were collected from 69 veterans of Operations Enduring Freedom or Iraqi Freedom (OEF/OIF) who had screened positive for hazardous drinking. The sample was 91.3% male and 65.2% Caucasian. Based on a structured interview, 58% of the sample met criteria for PTSD. RESULTS: The PTSD group scored higher than the non-PTSD group on scales measuring drinking to cope with anxiety and depression and similarly to the non-PTSD group on scales measuring social, enhancement and conformity motives. Coping and social motives were significantly correlated with adverse alcohol consequences. Overall, the PTSD group showed stronger relations between coping scales and aspects of alcohol misuse, relative to the non- PTSD group. CONCLUSION: These findings suggest first, that among heavy drinking OEF/OIF veterans there is a high base rate of PTSD. Second, coping motives are frequently reported in this population, and they seem to be related to a more severe pattern of alcohol-related consequences. These findings underscore the importance of assessing the interplay between PTSD and substance abuse in trauma-exposed samples.

PTSD symptoms, hazardous drinking, and health functioning among U.S.OEF and OIF veterans presenting to primary care.

Posttraumatic stress disorder (PTSD) and alcohol abuse both are negatively associated with health, and alcohol misuse may mediate the relationship between PTSD and functional health outcomes. The present study tested for such mediation using self-report measures of PTSD symptoms, hazardous alcohol use, and health functioning in 151 U.S. veterans (136 men and 15 women) of the wars in Iraq and Afghanistan recruited from a Veterans Affairs primary care clinic. Based on established cut scores, 39.1% screened positive for PTSD and 26.5% screened positive for hazardous drinking. PTSD symptoms and hazardous drinking were significantly correlated with each other and with health functioning. Hazardous drinking was found to partially mediate the relationship between PTSD and functional mental health, but not physical health.