Catecholamine Adrenergic Transmission and Adrenoceptors

Certain neurons can enzymatically produce L-dopa (L-dihydroxyphenylalanine) from the amino acid L-tyrosine. L-dopa is the parent substance of dopamine, norepinephrine, and epinephrine—the three natural catecholamines, which are enzymatically synthesized in this order. Dopamine (DA) is the final step of synthesis in neurons containing only the enzyme required for the first step (the aromatic L-amino acid decarboxylase). Dopamine is used as a transmitter by the dopaminergic neurons in the CNS and by autonomic neurons that innervate the kidney.

Norepinephrine (NE) is produced when a second enzyme (dopamine-fi-hydroxylase) is also present. In most sympathetic postgan-glionic nerve endings and noradrenergic central neurons, NE serves as the neurotransmitter along with the co-transmitters adenosine tri-phosphate (ATP), somatostatin (SIH), or neu-ropeptide Y(NPY).

Within the adrenal medulla (see below) and adrenergic neurons of the medulla ob-longata, phenylethanolamine N-methyltrans-ferase transforms norepinephrine (NE) into epinephrine (E).

The endings of unmyelinated sympathetic postganglionic neurons are knobby or varicose (^ A). These knobs establish synaptic contact, albeit not always very close, with the effector organ. They also serve as sites of NE synthesis and storage. L-tyrosine (^ A1) is actively taken up by the nerve endings and transformed into dopamine. In adrenergic stimulation, this step is accelerated by protein kinase A-mediated (PKA; ^ A2) phosphorylation of the responsible enzyme. This yields a larger dopamine supply. Dopamine is transferred to chromaffin vesicles, where it is transformed into NE (^ A3). Norepinephrine, the end product, inhibits further dopamine synthesis (negative feedback).

NE release. NE is exocytosed into the synaptic cleft after the arrival of action potentials at the nerve terminal and the initiation of Ca2+ influx (^ A4 and p. 50).

Adrenergic receptors or adrenoceptors (^ B). Four main types of adrenoceptors (a1, a2, | and |2) can be distinguished according to their affinity to E and NE and to numerous agonists and antagonists. All adrenoceptors respond to E, but NE has little effect on p2-adrenoceptors. Isoproterenol (isoprenaline) activates only ^-adrenoceptors, and phen-tolamine only blocks a-adrenoceptors. The activities ofall adrenoceptors are mediated by G proteins (^ p. 55).

Different subtypes (a1A, a1B, a1D) of a1-adrenoceptors can be distinguished (^ B1). Their location and function are as follows: CNS (sympathetic activity f), salivary glands, liver (glycogenolysis f), kidneys (alters threshold for renin release; ^ p. 184), and smooth muscles (trigger contractions in the arterioles, uterus, deferent duct, bronchioles, urinary bladder, gastrointestinal sphincters, and dilator pupillae).

Activation of a1-adrenoceptors (^ B1), mediated by Gq proteins and phospholipase C| (PLC|), leads to formation of the second messengers inositol tris-phosphate (IP3), which increases the cytosolic Ca2+ concentration, and diacylglycerol (DAG), which activates protein kinase C (PKC; see also p. 276). Gq protein-mediated a1-adrenoceptor activity also activates Ca2+-dependent K+ channels. The resulting K+ outflow hyperpolarizes and relaxes target smooth muscles, e.g., in the gastrointestinal tract.

Three subtypes (a2 A, a2 B, a2 C) of ^-adrenoceptors (^ B2) can be distinguished. Their location and action are as follows: CNS (sympathetic activity I, e.g., use of the a2 agonist clonidine to lower blood pressure), salivary glands (salivation I), pancreatic islets (insulin secretion I), lipocytes (lipolysis I), platelets (aggregation f), and neurons (presynaptic au-toreceptors, see below). Activated a2-adreno-ceptors (^ B2) link with Gi protein and inhibit (via ai subunit of Gi) adenylate cyclase (cAMP synthesis I, ^ p. 274) and, at the same time, increase (via the subunit of Gi) the open-probability of voltage-gated K+ channels (hy-perpolarization). When coupled with G0 proteins, activated a2-adrenoceptors also inhibit voltage-gated Ca2+ channels ([Ca2+]i I).

All p-adrenoceptors are coupled with a Gs protein, and its aS subunit releases cAMP as a second messenger. cAMP then activates pro

Adrenergic Transmission

tein kinase A (PKA), which phosphorylates different proteins, depending on the target cell type (^ p. 274).

NE and E work via pi-adrenoceptors (^ B3) to open L-type Ca2+ channels in cardiac cell membranes. This increases the [Ca2+]i and therefore produces positive chronotropic, dro-motropic, and inotropic effects. Activated Gs protein can also directly increase the open-

probability of voltage-gated Ca2+ channels in the heart. In the kidney, the basal renin secretion is increased via ^-adrenoceptors.

Activation of p2-adrenoceptors by epinephrine (^ B4) increases cAMP levels, thereby lowering the [Ca2+]i (by a still unclear mechanism). This dilates the bronchioles and blood vessels of skeletal muscles and relaxes the muscles of the uterus, deferent duct, and gastrointestinal tract. Further effects of p2-adrenoceptor activation are increased insulin secretion and glycogenolysis in liver and muscle and decreased platelet aggregation. Epi-nephrine also enhances NE release in nor-adrenergic fibers by way of presynaptic p2-adrenoceptors (^ A2, A5).

Heat production is increased via p3-adreno-C^ ceptors on brown lipocytes (^ p. 222).

NE in the synaptic cleft is deactivated by "X (^ A6 a - d):

m ! diffusion of NE from the synaptic cleft into £ the blood;

! extraneuronal NE uptake (in the heart, glands, smooth muscles, glia, and liver), and £ subsequent intracellular degradation of NE by Z catecholamine-O-methyltransferase (COMT) .y and monoamine oxidase (MAO); H ! active re-uptake of NE (70%) by the presyn-§ aptic nerve terminal. Some of the absorbed NE □ enters intracellular vesicles (^ A3) and is re-^ used, and some is inactivated by MAO; m ! stimulation of presynaptic ^-adrenoceptors (autoreceptors; ^ A 6d, 7) by NE in the synaptic cleft, which inhibits the further release ofNE.

Presynaptic a2-adrenoceptors can also be found on cholinergic nerve endings, e.g., in the gastrointestinal tract (motility |) and cardiac atrium (negative dromotropic effect), whereas presynaptic M-cholinoceptors are present on noradrenergic nerve terminals. Their mutual interaction permits a certain degree ofperiph-eral ANS regulation.

In alarm reactions, secretion of E (and some NE) from the adrenal medulla increases substantially in response to physical and mental or emotional stress. Therefore, cells not sympathetically innervated are also activated in such stress reactions. E also increases neuronal NE release via presynaptic ^-adrenoceptors (^ A2). Epinephrine secretion from the adrenal medulla (mediated by increased sympathetic activity) is stimulated by certain triggers, e.g., physical work, cold, heat, anxiety, anger (stress), pain, oxygen deficiency, or a drop in blood pressure. In severe hypoglycemia (<30mg/dL), for example, the plasma epi-nephrine concentration can increase by as much as 20-fold, while the norepinephrine concentration increases by a factor of only 2.5, resulting in a corresponding rise in the E/NE ratio.

The main task of epinephrine is to mobilize stored chemical energy, e.g., through lipolysis and glycogenolysis. Epinephrine enhances the uptake of glucose into skeletal muscle (^ p. 282) and activates enzymes that accelerate glycolysis and lactate formation (^ p. 72ff.). To enhance the blood flow in the muscles involved, the body increases the cardiac output while curbing gastrointestinal blood flow and activity (^ p. 75 A). Adrenal ep-inephrine and neuronal NE begin to stimulate the secretion of hormones responsible for replenishing the depleted energy reserves (e.g., ACTH; ^ p. 297 A) while the alarm reaction is still in process.

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