PubMed · 35090
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J W Hudson, L C Wang. 1979. Hibernation: endocrinologic aspects.. https://doi.org/10.1146/annurev.ph.41.030179.001443
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There are at least three isozymes (C alpha, C beta, and C gamma) of the mammalian catalytic (C) subunit of cAMP-dependent protein kinase (PKA) (Beebe, S., Oyen, O., Sandberg, M., Froysa, A., Hansson, V., and Jahnsen, T. (1990) Mol. Endocrinol. 4, 465-475). To compare the C gamma and C alpha isozymes, the respective cDNAs were expressed in permanently transformed Kin-8 PKA-deficient Y1 adrenal cells using the mouse metallothionein promoter. The recombinant C subunits were characterized as immunoreactive, zinc-inducible, cAMP-dependent kinase activities. In contrast to C alpha, histone was a better substrate than Leu-Arg-Arg-Ala-Ser-Leu-Gly (Kemptide) for C gamma. Furthermore, C gamma histone kinase activity was not inhibited by the protein kinase inhibitor peptide (5-24 amide), which has been widely used as a PKA-specific inhibitor. The major C gamma peak (type I) eluted from DEAE-Sepharose at a higher NaCl concentration (120 mM) than the C alpha type I eluted (70 mM). C gamma and C alpha type II eluted between 220 and 240 mM NaCl. C gamma required higher concentrations of cAMP than C alpha did for dissociation from the mutant type I holoenzyme. These differences provided a basis for the separation of the mutant RI-associated isozymes on DEAE-Sepharose. Both C alpha (41-42 kDa) and C gamma (39-40 kDa) were identified by a C subunit antibody after sodium dodecyl sulfate-polyacrylamide gel electrophoresis and immunoblot analysis. Zinc induced the PKA-mediated rounding phenotype in C gamma and C alpha clones, thereby restoring the cells to the parent Y1 adrenal cell phenotype. Collectively, these data indicate that C gamma is an active PKA C subunit but suggest that C gamma and C alpha have different protein and peptide recognition determinants.
Repeated exposure to stressful situations has been shown to increase individual reactivity to addictive drugs. However, the biological factors involved in such stress-induced changes are largely unknown. In this study, we investigated the role of corticosterone in the effects of restraint stress on the response to psychostimulants and opioids. The effects of repeated stress on amphetamine- and morphine-induced locomotor activity were compared in: (i) animals with an intact hypothalamo-pituitary-adrenal (HPA) axis; (ii) animals in which stress-induced corticosterone secretion was blocked by adrenalectomy, but who received exogenous corticosterone from a subcutaneous implant. The implanted pellets (50 mg) slowly release corticosterone producing a stable plasma level within the normal physiological range over a period of 20 days. Restraint stress increased the locomotor response to both amphetamine (1.5 mg/kg i.p.) and morphine (2 mg/kg s.c.) in animals with an intact HPA axis, but not in animals in which stress-induced corticosterone secretion was suppressed. These results suggest that corticosterone secretion may be one of the mechanisms by which repeated stress amplifies behavioral responses to amphetamine and morphine. Since an enhanced locomotor reactivity to addictive drugs has been found to be frequently associated with an enhanced vulnerability to drug self-administration, these findings point to a role for glucocorticoids in the susceptibility to drug abuse.
Neurosecretory vesicles of paraventricular corticotropin releasing factor (CRF) neurons increase in size after adrenalectomy (ADX) in parallel with an augmentation of their content in vasopressin (VP) immunoreactive sites. We have investigated in the Brattleboro rat model whether changes in vesicle size are related to elevated intravesicular concentrations of VP. Using quantitative immunoelectron microscopy, VP and CRF immunoreactive sites were assessed in the dense core vesicle compartment of CRF axon terminals in the median eminence. In heterozygous (control) rats, CRF was co-packaged with VP, and ADX induced a 3-fold increase in VP labeling intensity and produced a significant increase in the vesicle diameter. In homozygous rats lacking VP, only CRF immunoreactivity was detectable, and ADX was not accompanied by an increase in vesicle size. These observations suggest that the presence of VP is necessary for the ADX induced increase in vesicle size and that this increase might be needed to accommodate the excess of VP in the vesicle space.