Signals Activated by AR Subtypes

In most cases, it has been found that each member of an AR subfamily couples faithfully to a single G protein type. The a1-ARs (a1A, a1B, a1D) act through Gq/11 to increase intracellular Ca2+, a2-ARs (a2A, a2B, a2C) act through Gj to decrease cAMP, and P-ARs (P1, P2, P3) act through GS to increase cAMP. The dual G protein specificity observed with other GPCRs, such as angiotensin II receptors (which activate both Gq/11 and Gi families) (7), has not generally been observed with AR subtypes.

2.1. Multiple Effects Caused by Multiple Subtypes

The multiplicity of AR subtypes suggests that they may activate many different, redundant, or potentially conflicting signaling pathways, resulting in a multitude of different functional responses. This is in fact the case because AR activation causes effects ranging from contraction or relaxation of vascular smooth muscle; contraction of cardiac muscle; decreased motility of intestinal smooth muscle; release of energy stores from liver, fat, and skeletal muscle; and many others. Many of these different effects are simply caused by the presence or absence of particular AR subtypes in a particular tissue and are thus to be expected. For example, bronchial smooth muscle contains primarily P2-ARs, which cause relaxation; most vascular smooth muscles contain primarily a1-ARs, which cause contraction.

2.2. Unexpected Responses to Individual Subtypes

On the other hand, there are cases for which well-defined AR subtypes have been found to activate signaling pathways that would not normally be expected to be activated by that receptor. For example, although mitogen-activated protein kinase (MAPK) pathways were primarily thought to be activated by growth factor receptors with intrinisic tyrosine kinase activity (8), it quickly became clear that many GPCRs could also activate these pathways (9). Subsequently, it has been found that a1- (10), a2- (11), and P- (12) ARs all activate MAPKs in a variety of systems despite their specificity in coupling to different G proteins (a:/ Gq/11, a^Gj, P/GS), some of which stimulate opposing signals (Gj, GS). Part of this may be explained by independent effects of common Py-subunits (11), but this does not entirely explain the results because not all ARs activate MAPK in a single cell type (13), although they all undoubtedly release Py-subunits when activated. In addition, all three AR subfamilies have been reported to activate tyrosine kinase pathways (14,15), again possibly involving release of Py-sub-units.

The a1-ARs have also been reported to activate the Jak/Stat signaling pathway normally associated with cytokine receptors (16), similar to that observed with angiotensin II receptors, which have been much more extensively studied (17). Also, a1-ARs increase inositol phosphate formation in primary brain cell cultures through a pertussis toxin-sensitive G protein (18), despite the fact that none of the Gq/11 proteins are inactivated by pertussis toxin. Finally, a large array of transcriptional reporters were activated by stimulation of a1-ARs expressed in various cells (19,20) that were often insensitive to drugs thought to block downstream second messenger responses. Similar unexpected responses have been observed with P-ARs, for which coupling of P3-ARs to both GS and Gi has been suggested (21). Similarly, coupling of the P2-AR to Gi proteins appears to be important under some circumstances (22), and it has been suggested that activation of cAMP-dependent protein kinase switches the signaling specificity of this receptor from GS to Gi (23). Thus, it is clear that specific signaling pathways for ARs are still not completely understood.

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