Effects of guanine nucleotides and parathyroid hormone on inositol 1,4,5-trisphosphate metabolism in canine renal cortical tubular cell membranes.
Parathyroid hormone (PTH) and guanosine 5'-O-(3-thiotriphosphate) (GTP-gamma S) increase levels of the second messenger inositol 1,4,5-triphosphate (IP3) and other inositol phosphates (IP) in several membrane preparations of PTH-responsive cells. We present evidence here indicating that in a membrane preparation of canine renal cortical tubular cells bPTH-(1-84), bPTH-(1-34), [N-Leu8,18Tyr34]bPTH-(3-34)NH2, and the human PTH related peptide fragment hPTHrP-(1-34)NH2 all increase levels of inositol phosphate (IP) but [Tyr34]-bPTH-(7-34)NH2 and hPTHrP-(7-34)NH2 have no significant effects on IP accumulation. Increases in IPs are generally attributed to increased formation of IPs and appear to be mediated by a G protein. However, increased levels of IPs may also result from inhibition of the phosphatases are responsible for their metabolism. We investigated the effect of PTH and GTP-gamma S on the metabolism of IP3 in canine renal cortical tubular membranes. These membranes rapidly metabolize [3H]IP3 (47% at 15 s). Decreases in [3H]IP3 at all time points are accounted for quantitatively by increases in the sum of its breakdown products: [3H]IP2, [3H]IP1, and [3H]inositol. After 5 minutes of exposure to membranes, the vast majority of [3H]IP3 (84%) is converted to its terminal metabolite, [3H]inositol. GTP-gamma S (100 microM) inhibits the amount of [3H]IP3 metabolized in 15 s by 70% and reduces the amount of [3H]inositol ultimately formed in 5 minutes by 64%. ATP-gamma S, ATP, and 2,3-bisphosphoglycerate (100 microM) also inhibit [3H]IP3 hydrolysis in this preparation.(ABSTRACT TRUNCATED AT 250 WORDS)
Coleman
D T
DT
Department of Pharmacology, College of Physicians and Surgeons, Columbia University, New York, New York.
Morrow
B S
BS
Bilezikian
J P
JP
D019794:2,3-Diphosphoglycerate; D000255:Adenosine Triphosphate / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D004163:Diphosphoglyceric Acids / Q000494:pharmacology; D004285:Dogs; D005260:Female; D006150:Guanine Nucleotides / Q000494:pharmacology; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000494:pharmacology*; D015544:Inositol 1,4,5-Trisphosphate / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007684:Kidney Tubules / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D007700:Kinetics; D008297:Male; D010281:Parathyroid Hormone / Q000494:pharmacology*; D044162:Parathyroid Hormone-Related Protein; D010446:Peptide Fragments / Q000494:pharmacology; D011506:Proteins / Q000494:pharmacology; D019379:Teriparatide / Q000031:analogs & derivatives
D004163:Diphosphoglyceric Acids; D006150:Guanine Nucleotides; D010281:Parathyroid Hormone; D044162:Parathyroid Hormone-Related Protein; D010446:Peptide Fragments; D011506:Proteins; D019379:Teriparatide; D019794:2,3-Diphosphoglycerate; C022571:adenosine 5'-O-(3-thiotriphosphate); D016244:Guanosine 5'-O-(3-Thiotriphosphate); D015544:Inositol 1,4,5-Trisphosphate; D000255:Adenosine Triphosphate; C061438:parathyroid hormone (1-34)amide, Nle(8), Nle(18), Tyr(34)-