Page 152 - Basic _ Clinical Pharmacology ( PDFDrive )

138 SECTION II Autonomic Drugs

Both types of sympathomimetics, direct and indirect, ulti- G proteins are classified on the basis of their distinctive α subunits.
mately cause activation of adrenoceptors, leading to some or all G proteins of particular importance for adrenoceptor function
of the characteristic effects of endogenous catecholamines. The include G , the stimulatory G protein of adenylyl cyclase; G and
s
i
pharmacologic effects of direct agonists depend on the route of G , the inhibitory G proteins of adenylyl cyclase; and G and G ,
11
o
q
administration, their relative affinity for adrenoreceptor subtypes, the G proteins coupling α receptors to phospholipase C. The acti-
and the relative expression of these receptor subtypes in target vation of G protein-coupled receptors by catecholamines promotes
tissues. The pharmacologic effects of indirect sympathomimetics the dissociation of guanosine diphosphate (GDP) from the α
are greater under conditions of increased sympathetic activity and subunit of the cognate G protein. Guanosine triphosphate (GTP)
norepinephrine storage and release. then binds to this G protein, and the α subunit dissociates from
the β-γ unit. The activated GTP-bound α subunit then regulates
the activity of its effector. Effectors of adrenoceptor-activated α
■ MOLECULAR PHARMACOLOGY subunits include adenylyl cyclase, phospholipase C, and ion chan-
UNDERLYING THE ACTIONS OF nels. The α subunit is inactivated by hydrolysis of the bound GTP
to GDP and phosphate, and the subsequent reassociation of the
SYMPATHOMIMETIC DRUGS α subunit with the β-γ subunit. The β-γ subunits have additional
independent effects, acting on a variety of effectors such as ion
The effects of catecholamines are mediated by cell-surface recep- channels and enzymes.
tors. Adrenoceptors are typical G protein-coupled receptors Adrenoreceptors were initially characterized pharmacologically
(GPCRs; see Chapter 2). The receptor protein has an extracellular by their relative affinities for agonists; α receptors have the com-
N-terminus, traverses the membrane seven times (transmembrane parative potencies epinephrine ≥ norepinephrine >> isoproterenol,
domains) forming three extracellular and three intracellular and β receptors have the comparative potencies isoproterenol >
loops, and has an intracellular C-terminus (Figure 9–1). They are epinephrine ≥ norepinephrine. The presence of subtypes of these
coupled to G proteins that regulate various effector proteins. Each receptors were further characterized by molecular cloning. The
G protein is a heterotrimer consisting of α, β, and γ subunits. genes encoding these receptor subtypes are listed in Table 9–1.

Agonist

G q Phospholipase C

Ptdlns 4,5P 2

{
DAG
β γ
α q α q * +
Activated
GDP PKC PKC
Alpha 1 GTP
receptor IP 3
Ca -dependent +
2+
protein kinase

+ Free Stored
calcium calcium
Activated
protein kinase

FIGURE 9–1 Activation of α 1 responses. Stimulation of α 1 receptors by catecholamines leads to the activation of a G q -coupling protein. The
activated α subunit (α q *) of this G protein activates the effector, phospholipase C, which leads to the release of IP 3 (inositol 1,4,5-trisphosphate)
and DAG (diacylglycerol) from phosphatidylinositol 4,5-bisphosphate (PtdIns 4,5P 2 ). IP 3 stimulates the release of sequestered stores of calcium,
2+
2+
2+
leading to an increased concentration of cytoplasmic Ca . Ca may then activate Ca -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 α 1 -receptor activation.