Agonists to ions: Efficiency suggests a 'zipper' mechanism for nicotinic receptor activation

Agonists are classified by the strength at which they bind to their target sites (affinity) and their ability to activate receptors once bound to those sites (efficacy). Efficiency is a third fundamental agonist property that is a measure of the correlation between affinity and efficacy. Efficiency is the percent of agonist binding energy that is converted into energy for receptor activation ('gating'). In the muscle nicotinic acetylcholine receptor, agonists belong to families having discrete efficiencies of 54%, 51%, 42% or 35%. Efficiency depends on the size and composition of both the agonist and binding site, and can be estimated from, and used to interpret, concentration-response curves. A correlation between affinity and efficacy indicates that the agonist's energy changes that take place within binding and gating processes are linked. Efficiency suggests that receptors turn on and off by progressing through a sequence of energy-linked domain rearrangements, as in a zipper.

Molecular Docking Studies of Bioactive Compounds from Solenostemma Argel Leaf Extract as Potential Inhibitor for BCL-2 Antiapoptotic Proteins

This article deals with anticancer studies of phytochemicals identified from Solenostemma Argel leaf extract using GC-MS analysis and molecular docking studies. B cell lymphoma-2 (BCL-2) agonists are useful for regulating apoptosis which is essential for several cancers. The aim of the present study is to investigate the BCl-2 agonist property of phytochemicals from the extract of S. Argel using an Insilco approach. The docking on human BCL-2 protein was determined by GOLD 3.0.1 software. It is concluded from the studies that compound suggested by GCMS at RT 17.1 minute is 4,5,7-trihydroxy isoflavone showed best result with highest fitness index

Angiotensin Receptor II Type 1 and the Activation of Myosin Light-Chain Kinase and Protein Kinase C-βII. Mini Review

The involvement of the angiotensin II type 1 receptor in the Frank-Starling Law of the Heart, where the various activations are very limited, allows simple analysis of the kinase systems involved and thence extrapolation of the mechanism to that of angiotensin control of activation of cardiac and skeletal muscle contraction. The involvement of phosphorylation of the myosin light chain in the control of contraction is accepted but not fully understood. The involvement of troponin-I phosphorylation is also indicated but of unknown mechanism. There is no known signal for activation of myosin light chain kinase or Protein Kinase C-βII other than Ca2+/calmodulin but the former is constitutively active and thus has to be under control of a regulated inhibitor, the latter kinase may also be the same. Ca2+/calmodulin is not activated in Frank-Starling, i.e. there are no diastolic or systolic [Ca2+] changes. I suggest here that that the regulated inhibition is by myosin light chain phosphatase and/or β-arrestin. Angiotensin activation is by translocation of the β-arrestin from the sarcoplasm to the PM thus reducing its kinase inhibition action in the sarcoplasm, this reduced inhibition has been wrongly attributed to a mythical downstream agonist property of β-arrestin.

Angiotensin Receptor II type 1 and the activation of Myosin Light-Chain Kinase and Protein Kinase C-βII. Mini Review.

The involvement of the angiotensin II type 1 receptor in the Frank-Starling Law of the Heart, where the various activations are very limited, allows simple analysis of the kinase systems involved and thence extrapolation of the mechanism to that of angiotensin control of activation of cardiac and skeletal muscle contraction. The involvement of phosphorylation of the myosin light chain in the control of contraction is accepted but not fully understood. The involvement of troponin-I phosphorylation is also indicated but of unknown mechanism. There is no known signal for activation of myosin light chain kinase or Protein Kinase C-βII other than Ca2+/calmodulin but the former is constitutively active and thus has to be under control of a regulated inhibitor the latter kinase may also be the same. Ca2+/calmodulin is not activated in Frank-Starling, i.e. there are no diastolic or systolic [Ca2+] changes. I suggest here that that the regulated inhibition is by myosin light chain phosphatase and/or β-arrestin. Angiotensin activation is by translocation of the β-arrestin from the sarcoplasm to the PM thus reducing its inhibition in the sarcoplasm, this reduced inhibition has been wrongly attributed to a mythical downstream agonist property of β-arrestin.

Relaxation of Androgens on Rat Thoracic Aorta: Testosterone Concentration Dependent Agonist/Antagonist l-Type Ca2+ Channel Activity, and 5β-Dihydrotestosterone Restricted to l-Type Ca2+ Channel Blockade

Androgen vasorelaxing action is a subject of recent interest. We investigated the involvement of l-type voltage-operated Ca2+ channels (L-VOCCs), K+ channels, intracellular Ca2+ concentration ([Ca2+]i), and cAMP in the vasorelaxing effect of testosterone and 5β-dihydrotestosterone (5β-DHT) on rat thoracic aorta. Isolated aortic rings were used to study the vasorelaxing potency of testosterone and 5β-DHT on KCl- and noradrenaline-induced contractions. Patch-clamp was used to analyze androgen effects on Ca2+ inward and K+ outward currents. The fluorescence technique was used to evaluate [Ca2+]i in single myocytes; moreover, simultaneous measurements of [Ca2+]i and vascular contraction were evaluated. 5β-DHT was more potent than testosterone to relax KCl-induced contraction, but they were equipotent to relax noradrenaline contraction. l-type Ca2+ currents were blocked by nifedipine, both androgens, and an estrogen in a concentration-dependent manner, and the order of potency was: testosterone > nifedipine > 5β-DHT > 17β-estradiol. We observed that testosterone has different mechanism of action by the concentration range used: at nm concentrations it was a powerful L-VOCCs antagonist, whereas at μm concentrations it was observed that: 1) its Ca2+ antagonist property is reverted by increasing the l-type inward Ca2+ currents (Ca2+ agonist property); and 2) the [Ca2+]i and cAMP production was increased. The total K+ currents were unaffected by testosterone or 5β-DHT. The data show that 5β-DHT-induced vasorelaxation is due to its selective blockade on L-VOCCs (from nm to μm concentrations), but testosterone-induced vasorelaxation involves concentration-dependent additional mechanisms: acting as an L-VOCCs antagonist at low concentrations, and increasing [Ca2+]i and cAMP production at high concentrations.

The effect of anti-oestrogens on cell growth and progesterone receptor concentration in human endometrial cancer cells (Ishikawa)

ASTRACT The effect of two anti-oestrogens, 4-OH tamoxifen and ICI 164,384, on growth and progesterone receptor (PR) concentration was investigated in the endometrial carcinoma cell line, Ishikawa. Growth stimulation in response to 4-OH tamoxifen was antagonized by ICI 164,384, the latter having no agonist effect when used as a single agent. Similarly, ICI 164,384 antagonized oestradiol-stimulated cell growth. PR was significantly increased following treatment with 4-OH tamoxifen, this response being antagonized in the presence of ICI 164,384. Oestradiol increased PR, although to a lesser extent than did 4-OH tamoxifen;the effect of oestradiol on PR was also antagonized by ICI 164,384. Used as a single agent, ICI 164,384 induced a moderate but statistically significant increase in PR, thus demonstrating partial agonist activity. This agonist property of ICI 164,384 may provide a mechanism of maintaining PR, which is down-regulated during conventional progestin therapy, without undesirable mitogenic activity.