FIGURE 9–1 Activation of α1 responses. Stimulation of α1 receptors by catecholamines leads to the activation of a Gq-coupling protein. The activated α subunit (αq*) of this G protein activates the effector, phospholipase C, which leads to the release of IP3 (inositol 1,4,5-trisphosphate) and DAG (diacylglycerol) from phosphatidylinositol 4,5-bisphosphate (PtdIns 4,5P2). IP3 stimulates the release of sequestered stores of calcium, leading to an increased concentration of cytoplasmic Ca2+. Ca2+ may then activate Ca2+-dependent protein kinases, which in turn phosphorylate their substrates. DAG activates protein kinase C (PKC). GDP, guanosine diphosphate; GTP, guanosine triphosphate. See text for additional effects of α1-receptor activation.
TABLE 9–1 Adrenoceptor types and subtypes.
Likewise, the endogenous catecholamine dopamine produces a variety of biologic effects that are mediated by interactions with specific dopamine receptors (Table 9–1). These receptors are particularly important in the brain (see Chapters 21, 28, and 29) and in the splanchnic and renal vasculature. Molecular cloning has identified several distinct genes encoding five receptor subtypes, two D1-like receptors (D1 and D5) and three D2-like receptors (D2, D3, and D4). Further complexity occurs because of the presence of introns within the coding region of the D2-like receptor genes, which allows for alternative splicing of the exons in this major subtype. There is extensive polymorphic variation in the D4 human receptor gene. These subtypes may have importance for understanding the efficacy and adverse effects of novel anti-psychotic drugs (see Chapter 29).
A. Alpha Receptors
Alpha1 receptors are coupled via G proteins in the Gq family to phospholipase C. This enzyme hydrolyzes polyphosphoinositides, leading to the formation of inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) (Table 9–1, Figure 9–1). IP3 promotes the release of sequestered Ca2+ from intracellular stores, which increases cytoplasmic free Ca2+ concentrations that activate various calcium-dependent protein kinases. Activation of these receptors may also increase influx of calcium across the cell’s plasma membrane. IP3 is sequentially dephosphorylated, which ultimately leads to the formation of free inositol. DAG cooperates with Ca2+ in activating protein kinase C, which modulates activity of many signaling pathways. In addition, α1 receptors activate signal transduction pathways that stimulate tyrosine kinases. For example, α1 receptors have been found to activate mitogenactivated protein kinases (MAP kinases) and polyphosphoinositol3-kinase (PI-3-kinase).
Alpha2 receptors are coupled to the inhibitory regulatory protein Gi (Figure 9–2) that inhibits adenylyl cyclase activity and causes intracellular cyclic adenosine monophosphate (cAMP) levels to decrease. It is likely that not only α, but also the β-γ subunits of Gi contribute to inhibition of adenylyl cyclase. Alpha2 receptors use other signaling pathways, including regulation of ion channel activities and the activities of important enzymes involved in signal transduction. Indeed, some of the effects of α2 adrenoceptors are independent of their ability to inhibit adenylyl cyclase; for example, α2-receptor agonists cause platelet aggregation and a decrease in platelet cAMP levels, but it is not clear whether aggregation is the result of the decrease in cAMP or other mechanisms involving Gi-regulated effectors.
B. Beta Receptors