Physiological Basis of Adrenergic Pharmacology

The nervous system has two major components (Figure 1): the peripheral nervous system (PNS) and the central nervous system (CNS).7 Its functions include sensory input, integration of data, and motor output. The PNS is divided into sensory and motor divisions. The sensory division conducts information from the PNS to the CNS. The motor division conducts signals from the CNS to the PNS and is divided into the somatic (SNS) and autonomic nervous systems (ANS).7

Figure 1. The Nervous System.
Diagram showing the 2 major components of the nervous system.

The autonomic division of the PNS, i.e., the autonomic nervous system (ANS), controls involuntary responses through the coordinated actions of its sympathetic (adrenergic) and parasympathetic (cholinergic) branches.7 The parasympathetic branch of the ANS is responsible for conserving energy by regulating “rest and digest” responses. The sympathetic branch of the ANS mobilizes body systems to provide energy for “fight or flight” responses.

The sympathetic branch of the ANS is the major source of endogenous catecholamines, i.e., dopamine, norepinephrine, and epinephrine.8 Norepinephrine is synthesized primarily at sympathetic nerve endings and epinephrine is synthesized primarily in chromaffin cells of the adrenal medulla by sequential modification of tyrosine (Figure 2).8 Activation of the sympathetic branch and subsequent release of catecholamine is initiated by signals originating in the CNS.8

Figure 2. The Synthesis of Catecholamines: Dopamine, Norepinephrine, and Epinephrine.
Diagram showing the The synthesis of catecholamines.

The conversion of tyrosine to DOPA and of DOPA to dopamine occurs within the cytoplasm of neuronal cells. Dopamine is transported into synaptic vesicles where it is converted to norepinephrine. In adrenal medullary chromaffin cells, norepinephrine is transported or diffuses back into the cytoplasm where, under the influence of cortisol, it is converted to epinephrine. Epinephrine is then transported back into vesicles for storage until it is released by exocytosis.

Unlike sympathetic neurons, which synthesize and release norepinephrine at synapses on specific target organs, neuroendocrine (chromaffin) cells of the adrenal medulla synthesize epinephrine and release it directly into the bloodstream to be transported to target organs.8 In either case, to produce a biological/physiological effect, both norepinephrine and epinephrine must interact with adrenergic receptors (adrenoceptors), which have an organ-specific distribution.7-9

Adrenoceptors are selective for norepinephrine and epinephrine and are divided into three main classes, each of which has three subtypes; α11A, α1B, and α1D), α22A, α2B, and α2C), and β (β1, β2, and β3).8,9 Each of the adrenoceptor subtype is a member of the G protein-coupled receptor family (i.e., transmembrane receptors coupled to intracellular G proteins), so called because they bind guanine nucleotides, i.e., guanosine diphosphate (GDP) and triphosphate (GTP).8,9

G proteins are composed of α- and βγ-subunits. The binding of an agonist to a G protein-coupled adrenoceptor causes the exchange of GTP for GDP on the α-subunit.8,9 The α-GTP subunit dissociates from the βγ-subunit and interacts with effector proteins such as adenylate cyclase (Figure 3), phospholipase C, ion channels, and other proteins. Depending on the subtype of the adrenoceptor and the Gα isoform, Gα can stimulate or inhibit the activities of target organs.

Figure 3. Schematic Representation of Agonist-Gs Regulatory Protein Interaction.
Schematic representation of agonist-Gs regulatory protein interaction.

Major Gα isoforms include: Gαs (Gα stimulatory isoform), Gαi (Gα inhibitory isoform), Gαq (generally Gα stimulatory isoform), and Gα12/13 (a Gα isoform that interacts with diverse ion channels).8,9 Clearly, adrenoceptor subtypes bound to Gα isoforms activate different signaling pathways and have unique effects on target tissues (Table 2). G protein-mediated signals are terminated by the hydrolysis of GTP to GDP, catalyzed by α-subunit GTPase activity.8,9

Table 2. Actions of adrenoceptor and Gα signaling mediators.8,9
Adrenoceptor SubtypeSignaling MediatorsTissueEffects
α1Gαq/GαiVascular smooth muscleContraction
Genitourinary tract smooth muscleContraction
Gastrointestinal smooth muscleRelaxation
HeartIncreases inotropy and chronotropy
LiverGlycogenolysis and gluconeogenesis
α2GαiPancreatic β-cellsInhibits insulin secretion
NeuronsDecreases norepinephrine release

Feedback inhibition of sympathetic transmission
Vascular smooth muscleContraction
PlateletAggregation
β1GαsSinoatrial (SA) nodeIncreases heart rate (chronotropy)
Atrioventricular (AV) nodeIncreases conduction velocity
Cardiac muscleIncreases contraction (inotropy)
Kidney (juxtaglomerular cells)Renin release
Adipose tissueIncreases lipolysis
β2Gαs/GαiBronchial smooth muscleRelaxes bronchioles
Skeletal muscleGlycogenolysis
Gastrointestinal smooth muscleConstricts the sphincters

Relaxes the gut
Vascular smooth muscleVasodilation
UterusRelaxes uterine wall
BladderRelaxes bladder
Pancreatic β-cellsIncreases insulin release
LiverGlycogenolysis and gluconeogenesis
β3GαsAdipose tissueIncreases lipolysis

Prototypical signaling mechanism of α1-adrenoceptors primarily involves Gαq, a stimulatory Gα isoform. Gαq activates phospholipase C and increases intracellular Ca2+ ion concentrations.8,9 Increased Ca2+ ion concentrations activate diverse regulatory proteins that mediate physiological responses in various tissues. Alpha1-adrenoceptors are expressed primarily in vascular smooth muscle, genitourinary smooth muscle, gastrointestinal smooth muscle, heart, liver, and brain.8,9

Prototypical signaling mechanism of α2-adrenoreceptors primarily involves Gαi, an inhibitory Gα isoform. Gαi activation includes inhibition of adenylate cyclase that blocks the synthesis cAMP.8,9 Blocking cAMP synthesis decreases neuronal Ca2+ ion concentrations and neurotransmitter release from target neurons. Alpha2-adrenoceptors are expressed primarily in pancreatic β-cells, platelets, vascular smooth muscles, and at various sites in the CNS.8,9

Prototypical signaling mechanism of β-adrenoceptors primarily activate Gαs, a stimulatory Gα isoform.8,9 Gαs activates adenylate cyclase catalyzing the synthesis of cAMP. Increased cAMP activates protein kinases affecting a variety of intracellular proteins, including ion channels.8,9 Beta1-adrenoceptors are expressed primarily in the kidney and heart; β2-adrenoceptors in smooth muscle, skeletal muscle, liver, and heart; and β3-adrenoceptors in adipose tissue.8,9