{"id":531,"date":"2016-09-27T02:39:16","date_gmt":"2016-09-27T07:39:16","guid":{"rendered":"http:\/\/www.bocsci.com\/blog\/?p=531"},"modified":"2016-09-27T02:41:10","modified_gmt":"2016-09-27T07:41:10","slug":"modulating-effect-of-the-cardiotonic-steroid-marinobufagenin-on-slow-sodium-channels","status":"publish","type":"post","link":"https:\/\/www.bocsci.com\/blog\/modulating-effect-of-the-cardiotonic-steroid-marinobufagenin-on-slow-sodium-channels\/","title":{"rendered":"Modulating Effect of the Cardiotonic Steroid Marinobufagenin on Slow Sodium Channels"},"content":{"rendered":"

The objective of this study was to determine the\u00a0potential role of the cardiotonic steroid marinobufagenin\u00a0<\/a>in the mechanisms of nociceptive signal modulation. It is known that the first phase of the formation of a painful sensation is related to activation of tissue peripheral receptors that are capable of encoding\u00a0information not only about painful stimulation, but\u00a0also about signals of other modalities. Nociceptive signals emerge in free nerve endings innervated by A\u00a0and\u00a0C afferents of nociceptive neurons of dorsal ganglia.\u00a0Slow sodium channels (Na\u03bd<\/sub>1.8) insensitive to tetrodotoxin, which play an exclusive role in encoding\u00a0nociceptive signals, have been identified in membranes of nociceptive neurons. Therefore, search for\u00a0the specific blocker of these channels is important not\u00a0only for clarification of the mechanisms of sensory\u00a0information encoding, but also for medical practice.<\/p>\n

\"470-42-8\"<\/a><\/p>\n

Structure of marinobufagenin – CAS 470-42-8<\/a><\/p>\n

It is known that the target for endogenous\u00a0marinobufagenin is Na+<\/sup>,\u00a0K+<\/sup>\u00a0ATPase. In addition to its main pump function, this enzyme can also\u00a0function as a signal transducer. Therefore, the\u00a0target for the agent studied may be Na+<\/sup>,\u00a0K+<\/sup>\u00a0ATPase\u00a0(transducer\u0002mediated effect), as well as the amino\u00a0acid sequence of the Na\u03bd<\/sub>1.8\u00a0channel (activation of a\u00a0\u201cmodulated receptor\u201d).<\/p>\n

In the present study, it has been proved that\u00a0marinobufagenin, acting at a low, \u201cendogenous\u201d concentration, is capable of reducing the voltage sensitivity of the activation gate structure of Na\u03bd<\/sub>1.8\u00a0channels.\u00a0We will explore the molecular\u00a0mechanism of this effect\u00a0in our following studies.<\/p>\n

The effect of the cardiotonic steroid marinobufagenin from the class of bufadienolides on Na\u03bd<\/sub>1.8\u00a0sodium\u00a0channels was studied using the patch clamp\u00a0method.\u00a0We have modified this method in order to measure the\u00a0effective charge value of the activation gate structure of\u00a0slow sodium channels. Experiments were carried\u00a0out on cultured sensory neurons isolated from the\u00a0areas L5<\/sub>\u2013S1 <\/sub>of the spinal cord ganglia of newborn\u00a0Wistar rats with the use of standard solutions. Cultivation of isolated neurons for 2 h in the standard culture media with the use of \u0421\u041e2<\/sub>\u00a0temperature\u0002controlled chamber allows obtaining intact cells.<\/p>\n

The results were processed statistically using Student\u2019s t test. The differences were considered significant at \u0440 \u2264 0.05.<\/p>\n

The responses of Na\u03bd<\/sub>1.8\u00a0slow sodium channels\u00a0were measured in the control and after application of\u00a0marinobufagenin to the culture medium at a concentration of 10 nmol\/L. The experimental agent reduced\u00a0the amplitude of the currents. This was caused\u00a0mainly by the so\u0002called \u201crun\u0002down effect\u201d slightly\u00a0limiting the applicability of the patch clamp method.\u00a0The voltage sensitivity of the activation gate structure\u00a0of slow sodium channels was estimated by the modified Almers method, giving satisfactory measurement\u00a0of the effective charge value (Z<\/i><\/em>eff<\/sub>) of the activation gate\u00a0structure of slow sodium channels. This is due to a\u00a0rather slow development of Na\u03bd<\/sub>1.8 channel conductivity inactivation. The tangent of the slope\u00a0angle of the regression line determines the limiting\u00a0logarithmic sensitivity to voltage variation of the channel gate structure.<\/p>\n

A significant (p < 0.05) decrease in the effective\u00a0charge value (Zeff <\/sub>= 4.7 \u00b1\u00a00.4, n = 15) after application\u00a0of the steroid in comparison to the control (Zeff<\/sub>\u00a0=6.8 \u00b1\u00a00.4, n = 15) has been found in studying the effect\u00a0of marinobufagenin on the membrane of nociceptive\u00a0neuron.<\/p>\n

Pharmacological agents capable of reducing the\u00a0nociceptors excitability due to a decrease in the voltage sensitivity of the activation gate structure of\u00a0Na\u03bd<\/sub>1.8\u00a0slow sodium channels could play the role of\u00a0analgesics. Our data suggest that marinobufagenin\u00a0could play the role of the modulator of slow sodium\u00a0channel activity. The discovered effect of the reduction\u00a0of\u00a0Na\u03bd<\/sub>1.8\u00a0channel voltage sensitivity by marinobufagenin may be caused by one of the two mechanisms.\u00a0The first of them, transducer\u0002mediated one, is possibly triggered by the effect of the experimental agent on\u00a0its well\u0002known molecular target, Na+<\/sup>,\u00a0K+ <\/sup>ATPase\u00a0linked to slow sodium channels. The second mechanism may be activated by the direct interaction of\u00a0marinobufagenin with Na\u03bd<\/sub>1.8\u00a0channels. Further\u00a0experiments will allow choosing one of these alternative hypotheses. However, it is evident that any of the\u00a0two possible mechanisms of action of the given bufadienolide would lead to a decrease in nociceptor excitability. The physiological significance of this effect\u00a0cannot be overestimated, because it is known that the\u00a0endogenous cardiotonic steroid ouabain is a strong\u00a0analgesic. Another specific modulator of nociceptive neuron membrane excitability, comenic acid,\u00a0which affects Na\u03bd<\/sub>1.8\u00a0channels by selectively binding to\u00a0the specific receptor, also could successfully\u00a0play the role of a safe analgesic capable of replacing\u00a0opiates. All these data suggest that the study of the\u00a0physiological role of endogenous marinobufagenin\u00a0deserves close attention.<\/p>\n

Reference\uff1a<\/h4>\n

N. Shelykh, V. B. Plakhova, S. A. Podzorova, A. Ya. Bagrov, and B. V. Krylov. Doklady Biological Sciences, 2014, Vol. 458, pp. 278\u2013280<\/p>\n

 <\/p>\n

Related \u00a0products\uff1a<\/h4>\n
<\/div>
<\/th><\/th><\/th><\/th><\/th><\/tr><\/thead>
CAS Number <\/td>Product Name <\/td>Molecular Formula <\/td>Molecular Weight <\/td>Description <\/td><\/tr>
470-42-8 <\/td>marinobufagenin<\/a><\/td>C24H32O5 <\/td>400.52 <\/td>Marinobufagenin (marinobufagin) is a cardiotonic bufadienolide steroid secreted by the toad Bufo rubescens and other related species such as Bufo marinus. It is a vasoconstrictor with effects similar to digitalis. <\/td><\/tr><\/tbody><\/table><\/div>\n","protected":false},"excerpt":{"rendered":"

The objective of this study was to determine the\u00a0potential role of the cardiotonic steroid marinobufagenin\u00a0in the mechanisms of nociceptive signal modulation. It is known that the first phase of the […]<\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":[],"categories":[181],"tags":[320,318,319],"_links":{"self":[{"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/posts\/531"}],"collection":[{"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/comments?post=531"}],"version-history":[{"count":3,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/posts\/531\/revisions"}],"predecessor-version":[{"id":535,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/posts\/531\/revisions\/535"}],"wp:attachment":[{"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/media?parent=531"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/categories?post=531"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/tags?post=531"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}