Implications of post-pneumonectomy compensatory lung growth in pulmonary physiology and disease

In a number of species, partial pneumonectomy initiates hormonally regulated compensatory growth of the remaining lung lobes that restores normal mass, structure and function. Compensation is qualitatively similar across species, but differs with gender, age and hormonal status. Although the biology of response is best characterized in rats, dogs have proven valuable in defining post-operative physiological adaptations. Most recently, mice were recognized to offer unique opportunities to explore the genetic basis of the response, as well as to evaluate associated detrimental effects of pathophysiological significance in animals exposed to carcinogens. The pneumonectomy model thus offers powerful insight concerning adaptive organ growth

Two Classes of cAMP Analogs Which Are Selective for the Two Different cAMP-Binding Sites of Type II Protein Kinase Demonstrate Synergism When Added Together to Intact Adipocytes

Twenty-five cyclic nucleotide analogs were tested individually to act as lipolytic agents and to activate adipocyte protein kinase. The lipolytic potency of individual analogs correlated better with their K(a) for protein kinase and their lipophilicity rather than with either parameters alone. Some of the most potent lipolytic analogs had high I50 values for the particulate low K(m) cAMP phosphodiesterase suggesting that their effect was not due to raising endogenous cAMP levels through inhibition of phosphodiesterase. The most potent lipolytic analogs contained a thio moiety at the C-8 or C-6 position. These analogs exhibited concave upward dose-response curves. At high concentrations some analogs were as effective as optimal concentrations of epinephrine in stimulating glycerol release. The regulatory subunit of protein kinase has two different intrachain cAMP-binding sites and cAMP analogs modified at the C-8 position (C-8 analogs) are generally selective for Site 1 and analogs modified at the C-6 position (C-6 analogs) are generally selective for Site 2 (Rannels, S.R., and Corbin, J.D. (1980) J. Biol. Chem. 255, 7085-7088). Thus, C-8 and C-6 analogs were tested in combination to stimulate lipolysis in intact adipocytes and to activate protein kinase in vitro. Each process was stimulated synergistically by a combination of a C-6 and C-8 analog. Two C-8 analogs or two C-6 analogs added together did not cause synergism of either process. For both lipolysis and protein kinase activation, C-8 thio analogs acted more synergistically than C-8 amino analogs when incubated in combination with C-6 analogs, a characteristic of type II protein kinase. It is concluded that the observed synergism of lipolysis is due to binding of cAMP analogs to both intrachain sites and that it is the type II protein kinase isozyme which is responsible for the lipolytic response

Microheterogeneity of Type II cAMP-Dependent Protein Kinase in Various Mammalian Species and Tissues

Excluding autophosphorylated species, at least six forms of the regulatory subunit of type II cAMP-dependent protein kinase (R(II)) from various mammalian tissues were identified by sodium dodecyl sulfate (SDS) gel electrophoresis of purified samples and of crude preparations photoaffinity labeled with 8-azido[32P] cAMP and by gel filtration. After autophosphorylation some heart R(II) forms termed type IIA (bovine, porcine, equine, and dog) shifted to a more slowly migrating band on SDS gels while others termed type IIB (rat, guinea pig, rabbit, and monkey) did not detectably shift. Both subclasses of R(II) exhibited variation in apparent M(r) on SDS gels. Bovine and porcine heart nonautophosphorylated R(II) had M(r) 56,000 and the autophosphorylated R(II) had M(r) 58,000, while dog and equine heart R(II) had M(r) 54,000 and 56,000 for these bands, respectively. Rat heart R(II) had M(r) 56,000 while rabbit and guinea pig heart R(II) had M(r) 52,000. More than one R(II) was found in different tissues of the same species. Rabbit skeletal muscle contained a M(r) 56,000 IIB form. Bovine lung contained almost equal amounts of a IIA form apparently identical to that of bovine heart and a M(r) 52,000 IIB form similar to that which predominated in bovine brain. Rat adipose tissue, brain, and monkey heart contained predominantly a M(r) 51,000 IIB form. The rat liver M(r) 56,000 IIB form chromatographed differently from all other R(II) tested by gel filtration. Several lines of evidence indicated that the various forms of R(II) were not derived from one another through proteolysis or other processes. Each of the type II forms rapidly incorporated 0.3-1.0 mol of 32P per mol of subunit when incubated with [γ-32P]ATP and C subunit. Four of the forms tested were similar in the cAMP concentration dependence for activation of their corresponding holoenzymes and inhibited C subunit about equally. Each exhibited two components of [3H]cAMP dissociation, indicating two intrachain cAMP-binding sites, and the dissociation rates for the respective sites, and the dissociation rates for the respective sites were similar