Document Detail

Evidence that PKA activity is constitutively activated in human GH-secreting adenoma cells in a patient with Carney complex harbouring a PRKAR1A mutation.
MedLine Citation:
PMID:  19178533     Owner:  NLM     Status:  MEDLINE    
CONTEXT: The GHRH-protein kinase A (PKA) signalling pathway is essential for cell proliferation and GH synthesis/secretion in somatotrophs. An inactivating mutation of PRKAR1A is one of the causes of somatotrophinoma in Carney complex (CNC). The basal PKA activity of somatotroph adenoma cells from CNC has not been evaluated because of a limited amount of available tissue. OBJECTIVE: This study examined how the PRKAR1A mutation affects the PKA signalling pathway in a human somatotrophinoma with a PRKAR1A mutation. DESIGN AND SETTING: Somatotrophinoma cells from a 40-year-old male patient with CNC were used. The patient had a novel somatic heterozygous germline frameshift mutation (227delT) in PRKAR1A leading to a premature stop codon. The tumour showed loss of heterozygosity (LOH) at 17q23-24. Primary cultured adenoma cells were subjected to electrophysiological experiments to evaluate PKA signalling in individual cells. RESULTS: GHRH did not increase the nonselective cation current or the voltage-gated calcium current in these adenoma cells, in contrast to nonadenomatous somatotroph cells in which these currents increase through the PKA pathway. Application of a PKA inhibitor inhibited the basal currents in these adenoma cells, results that were not observed in nonadenomatous somatotrophs. These data indicate that the basal currents are already increased and cannot be further increased by GHRH. CONCLUSIONS: The results demonstrate that PKA is activated at the basal state in these adenoma cells. The data also show that both the nonselective cation current and the voltage-gated calcium current, vital regulators of GH secretion downstream of PKA, are maximally increased in these cells. These maximally increased currents probably account for the excessive GH secretion.
Koji Takano; Junko Yasufuku-Takano; Koji Morita; Shigetoshi Mori; Mao Takei; Robert Yoshiyuki Osamura; Akira Teramoto; Toshiro Fujita
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Publication Detail:
Type:  Case Reports; Journal Article; Research Support, Non-U.S. Gov't     Date:  2008-10-21
Journal Detail:
Title:  Clinical endocrinology     Volume:  70     ISSN:  1365-2265     ISO Abbreviation:  Clin. Endocrinol. (Oxf)     Publication Date:  2009 May 
Date Detail:
Created Date:  2009-04-02     Completed Date:  2009-07-30     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0346653     Medline TA:  Clin Endocrinol (Oxf)     Country:  England    
Other Details:
Languages:  eng     Pagination:  769-75     Citation Subset:  IM    
Department of Nephrology and Endocrinology, University of Tokyo Faculty of Medicine, Hongo Bunkyo-ku, Tokyo, Japan.
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MeSH Terms
Base Sequence
Calcium Channels / metabolism
Codon, Nonsense
Cyclic AMP-Dependent Protein Kinase RIalpha Subunit / genetics*
Cyclic AMP-Dependent Protein Kinases / metabolism*
DNA Mutational Analysis
DNA, Neoplasm / genetics
Enzyme Activation
Frameshift Mutation
Germ-Line Mutation
Growth Hormone-Secreting Pituitary Adenoma / enzymology*,  genetics*,  metabolism
Lentigo / enzymology*,  genetics*,  metabolism
Multiple Endocrine Neoplasia / enzymology*,  genetics*,  metabolism
Reg. No./Substance:
0/Calcium Channels; 0/Codon, Nonsense; 0/Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; 0/DNA, Neoplasm; 0/PRKAR1A protein, human; EC AMP-Dependent Protein Kinases

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