Cushing's Syndrome and Fetal Features Resurgence in Adrenal Cortex–Specific Prkar1a Knockout Mice

Carney complex (CNC) is an inherited neoplasia syndrome with endocrine overactivity. Its most frequent endocrine manifestation is primary pigmented nodular adrenocortical disease (PPNAD), a bilateral adrenocortical hyperplasia causing pituitary-independent Cushing's syndrome. Inactivating mutations in PRKAR1A, a gene encoding the type 1 α-regulatory subunit (R1α) of the cAMP–dependent protein kinase (PKA) have been found in 80% of CNC patients with Cushing's syndrome. To demonstrate the implication of R1α loss in the initiation and development of PPNAD, we generated mice lacking Prkar1a specifically in the adrenal cortex (AdKO). AdKO mice develop pituitary-independent Cushing's syndrome with increased PKA activity. This leads to autonomous steroidogenic genes expression and deregulated adreno-cortical cells differentiation, increased proliferation and resistance to apoptosis. Unexpectedly, R1α loss results in improper maintenance and centrifugal expansion of cortisol-producing fetal adrenocortical cells with concomitant regression of adult cortex. Our data provide the first in vivo evidence that loss of R1α is sufficient to induce autonomous adrenal hyper-activity and bilateral hyperplasia, both observed in human PPNAD. Furthermore, this model demonstrates that deregulated PKA activity favors the emergence of a new cell population potentially arising from the fetal adrenal, giving new insight into the mechanisms leading to PPNAD

Protein field effect on the dark state of 11-cis Retinal in Rhodopsin by Quantum Monte Carlo / Molecular Mechanics

"The accurate determination of the geometrical details of the dark state of 11-cis Retinal in Rhodopsin represents a fundamental step for the rationalization of the protein role in the optical spectral tuning in the vision mechanism. We have calculated geometries of the full Retinal Protonated Schiff base chromophore in gas phase and in protein environment using the correlated Variational Monte Carlo method. The Bond Length Alternation of the conjugated carbon chain of the chromophore in gas phase shows a significant reduction when moving from the f-ionone ring to the nitrogen whereas, as expected, the protein environment reduces the electronic conjugation. The proposed dark state structure is fully compatible with solid-state NMR data reported by Carravetta et. al. [J. Am. Chem. Soc. 2004, 126, 3948-3953]. TDDFT\/B3LYP calculations on such geometries show a blue opsin shift of 0.28 and 0.24 eV induced by the protein for S1 and S2 states, consistently with literature spectroscopic data. The effect of the geometrical distortion alone is a red shift of 0.21 and 0.16 eV with respect to the optimized gas phase chromophore. Our results open new perspectives for the study of the properties of chromophores in their biological environment using correlated methods.