Novel signal transduction pathways coupling beta(2)-adrenoceptor to its cellular effects in heart muscle
Authors
Advisor
Date
Embargo until
Language
Book title
Publisher
Peer Reviewed
Type
Research Area
Jurisdiction
Collections
Other Titles
See at
Abstract
This dissertation focuses on the signal transduction mechanism of {dollar}\beta\sb1{dollar}- and {dollar}\beta\sb2{dollar}-adrenoceptor ({dollar}\beta\sb1{dollar}AR and {dollar}\beta\sb2{dollar}AR) subtypes and their modulatory effects on cardiac excitation-contraction coupling. We demonstrated that both {dollar}\beta\sb1{dollar}AR and {dollar}\beta\sb2{dollar}AR functionally coexist in rat ventricular myocytes but that stimulation of these receptor subtypes elicits qualitatively different cellular responses. {dollar}\beta\sb2{dollar}AR stimulation induced by zinterol (ZINT) or by isoproterenol in the presence of the selective {dollar}\beta\sb1{dollar}AR antagonist, CGP 20712A, increased contraction amplitude to about the same extent as {dollar}\beta\sb1{dollar}AR stimulation induced by norepinephrine (NE). {dollar}\beta\sb1{dollar}AR stimulation has a potent effect to abbreviate the durations of the contraction and Ca{dollar}\sb{lcub}\rm i{rcub}{dollar} transient; in contrast, {dollar}\beta\sb2{dollar}AR stimulation has only a minor relaxation effect. In addition, {dollar}\beta\sb1{dollar}AR, but not {dollar}\beta\sb2{dollar}AR stimulation, increases the diastolic Ca{dollar}\sp{lcub}2+{rcub}{dollar} level and evokes spontaneous Ca{dollar}\sb{lcub}\rm i{rcub}{dollar} oscillations. {dollar}\beta\sb1{dollar}AR and {dollar}\beta\sb2{dollar}AR also differ in their effects on I{dollar}\sb{lcub}\rm Ca{rcub}{dollar}: whereas both {dollar}\beta\sb1{dollar}AR and {dollar}\beta\sb2{dollar}AR stimulation increase the peak I{dollar}\sb{lcub}\rm Ca{rcub}{dollar} amplitude to a similar extent, only {dollar}\beta\sb2{dollar} markedly prolongs the I{dollar}\sb{lcub}\rm Ca{rcub}{dollar} inactivation time; accordingly, {dollar}\beta\sb2{dollar}AR stimulation prolongs the action potential duration to a greater extent than {dollar}\beta\sb1{dollar}AR stimulation. Subsequent studies in rat ventricular myocytes have demonstrated that while both {dollar}\beta\sb1{dollar}AR and {dollar}\beta\sb2{dollar}AR stimulation increase total cellular cAMP to a similar extent, the effects of {dollar}\beta\sb2{dollar}AR stimulation on Ca{dollar}\sb{lcub}\rm i{rcub}{dollar} transient and contraction are largely dissociated from the cAMP increase. In addition, {dollar}\beta\sb2{dollar}AR stimulation does not result in phosphorylated phospholamban to the same extent as does {dollar}\beta\sb1{dollar}AR stimulation. These results suggest that {dollar}\beta\sb2{dollar}AR might be coupled to signaling pathway(s) other than the G{dollar}\sb{lcub}\rm s{rcub}{dollar}-mediated activation of adenylyl cyclase. This is further supported by the observation that pertussis toxin (PTX) pretreatment specifically potentiates the {dollar}\beta\sb2{dollar}AR evoked increases in I{dollar}\sb{lcub}\rm Ca{rcub}{dollar}, Ca{dollar}\sp{lcub}2+{rcub}{dollar} transient and contraction but not that of {dollar}\beta\sb1{dollar}AR stimulation. Thus, in the absence of PTX, substantial coupling occurs between {dollar}\beta\sb2{dollar}AR and a PTX-sensitive G-protein, exerting a negative feedback on the cardiac responses to {dollar}\beta\sb2{dollar}AR stimulation. Apparently, the distinct {dollar}\beta{dollar}AR subtype actions reside at least in part, in the different receptor-G protein interactions. The activation of more than a single G protein during {dollar}\beta\sb2{dollar}AR stimulation, leading to functionally opposite effects, may provide a mechanism to protect the heart from Ca{dollar}\sp{lcub}2+{rcub}{dollar} overload and arrhythmias during the response to stress.