Interactions between the effects of adenosine or 2‐chloro‐adenosine (CADO) and the effects of substances that interfere with the phosphoinositides/protein kinase C transducing system or with the adenylate cyclase transducing system, on endplate potentials (e.p.ps), were investigated. The preparation used was the innervated sartorius muscle of the frog in which twitches had been prevented with high magnesium concentrations.

The activator of protein kinase C, 4β‐phorbol‐12,13‐diacetate (PDAc), reversibly increased the amplitude and the quantal content of e.p.ps and attenuated the inhibitory effects of adenosine and CADO on e.p.p. amplitude. The affinity of the adenosine receptor antagonist, 8‐phenyltheophylline, was not modified by PDAc.

The phorbol ester 4α‐phorbol‐12,13‐didecanoate, which does not activate protein kinase C, did not modify either e.p.p. amplitude or the inhibitory effect of adenosine on e.p.ps.

The inhibitor of protein kinase C, polymyxin B, reversibly decreased the amplitude and the quantal content of e.p.ps, prevented the enhancement caused by PDAc on e.p.p. amplitude, but did not modify the inhibitory effect of adenosine on e.p.ps. H‐7, another inhibitor of protein kinases, also decreased e.p.p. amplitude but did not modify the effect of PDAc on the amplitude of e.p.ps.

Lithium chloride, which alters phosphoinositide signal transduction by inhibiting the breakdown of inositol phosphates, reversibly increased the amplitude and the quantal content of the e.p.ps. In the presence of adenosine or CADO the effect of lithium on e.p.p. amplitude was markedly attenuated.

The activator of adenylate cyclase, forskolin, reversibly increased the amplitude and the quantal content of the e.p.ps. MDL 12,330A, an inhibitor of adenylate cyclase, irreversibly decreased e.p.p. amplitude, an effect which was prevented by forskolin. Neither forskolin nor MDL 12,330A modified the inhibitory effect of adenosine on e.p.ps.

The results suggest that the phosphoinositides/protein kinase C transducing system, but not the adenylate cyclase transducing system, might be involved in the inhibitory effect of adenosine on neuromuscular transmission.

EndocrineQ3 · MEDICINE

Potentiation of Genomic Actions of Estrogen by Membrane Actions in MCF-7 Cells and the Involvement of Protein Kinase C Activation

Q3 · MEDICINE

Article

Author: Nino Devidze ; Lee-Ming Kow ; Donald W Pfaff

It is now well established that estrogens (E) have at least two kinds of actions: genomic and nongenomic. But the relationship between these actions has hardly been explored. In this study we investigated this relationship in MCF-7 cells, a human breast cancer cell line, and explored the possible involvement of protein kinase C (PKC) signaling pathways. For this purpose a two-pulse paradigm was used: cells were treated with 17beta-estradiol (E), E conjugated with bovine serum albumin (E-BSA or fE'), or other test agents in the first pulse and with E in the second pulse following a 4-h interval. An E-BSA+E paradigm was used to show that replacement of E with the membrane-impermeable E-BSA in the first pulse could potentiate genomic actions of E, in the second pulse. To investigate involvement of signaling pathways, two PKC activators, phorbol 12,13-diacetate (PDAc) or phorbol 12-myristate 13-acetate (PMA), and inhibitors (chelerythrine chloride and H7-dihydrochloride) were used to replace E or E-BSA in the first pulse. PDAc was as effective as E or E-BSA in potentiating the genomic action of E in the second pulse, while PMA was almost without an effect. Conversely, the potentiating effects of E-BSA and PDAc were blocked by chelerythrine chloride but, interestingly, not by H7. The exact reason underlying these differences is not known. In summary, in MCF-7 cells a membrane action of E can potentiate a later genomic action and involves PKC signaling.

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Pancreatic Ductal Adenocarcinoma	Preclinical	KR	ImmuneMed, Inc.	11 Aug 2024

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