he PKA signaling pathway. Of the three beta receptors, beta1 and beta2 are the better understood systems. The highest levels of beta1 are found in the heart and brain; beta2 is expressed in the heart, lung and other tissues. Beta2, due to its role in smooth muscle relaxation, has been the target for the development of short- and long-acting agonists used in the treatment of asthma. Short-acting agonists - 3 to 6 hours duration of action - include the commonly-used albuterol, fenoterol and the non-selective isoproterenol. The long-acting agonists - more than 12 hours duration of action - include salmeterol and formoterol. Safety issues are associated with both classes of agonists. In United States and Canada the use of long-acting agonists in patients with severe asthma is recommended in combination with inhaled corticosteroids. Both receptors are important for the stimulation of cardiac performance. PKA signaling exerts a plethora of effects; among its targets in cardiac myocytes are proteins involved in excitation-contraction coupling. Acute activation of the receptors following ventricular dysfunction, while initially beneficial, can lead to heart failure if it becomes chronic. Receptor desensitization is a hallmark of heart failure but its exact role in the condition is still to be determined. Beta-blockers, which compete with catecholamine binding to counteract excessive signaling and by the same token, allow the system to 're-sensitize', are the main therapeutics used for treatment. Some beta-blockers are selective for beta1 receptor while non-selective drugs can inhibit both beta1 and beta2 receptors. A benefit of the beta1 selective drugs is that, at least in low doses, they do not interfere with the bronchodilator action of the beta2 receptor. Caution is nonetheless necessary for patients with bronchospastic diseases. Beta-blockers which have been in use for over 50 years are generally safe; they have been prescribed for a range of cardiovascular and some non-cardiovascular disorders. It has to be mentioned here that the notion of agonist and antagonist are somehow misleading. Subtle differences in the conformation of receptors upon binding and/or engagement of particular signaling modules while antagonizing others can result in a multiplicity of alternative signaling events and much remains to be learned about the details regarding the responses of and signaling via beta adrenergic receptors. To see the ontology report for annotations, GViewer and download, click here.
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