5 Activation of alpha1-adrenergic responses Activation of alpha1-adrenergic responses. Stimulation of alpha1-adrenergic receptors by norepinephrine leads to the activation of a Gq coupling protein. The alpha subunit 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 4,5-P2). 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. alpha1-adrenergic receptors cause contraction of smooth muscle in the following organs:Eye: iris radial dilator muscle contraction (mydriasis - dilation)Arterioles: (coronary, skin, skeletal muscle, cerebral, pulmonary, abdominal, salivary gland, and renal)Stomach and Intestine: contraction of sphinctersGlandular Secretion (lacrimal(increase), salivary(increase), bronchial(decrease), pancreatic(decrease), mucosal(decrease), and sweat(palms sympathetic increase))Pilomotor muscles: contraction (goose pimples)Bladder neck: sphincter contractionSex Organs, Male: ejaculationSex Organs, Female: if pregnant uterus contraction.
6 Inhibition of adenylyl cyclase by agonists that bind to alpha2-adrenergic receptors. Alpha2 adrenoceptor ligands inhibit adenylyl cyclase by causing dissociation of the inhibitory G protein, Gi, into its subunits; ie, an alphai subunit charged with GTP and a beta-gamma unit. The mechanism by which these subunits inhibit adenylyl cyclase is uncertain. alpha2-adrenergic receptors cause specific actions in the following organs:Arterioles: (presynaptic alpha2-receptors cause decreased release and synthesis of catecholamines).Stomach and Intestine: decrease motilityPancreas: decreased release of insulinBrain (cardiovascular control center): activation of alpha2-receptors by NE causes increased parasymathetic outflow and decreased sympathetic outflow.
8 Activation of adenylyl cyclase by agonists that bind to beta1-adrenergic receptors. Binding to beta1-adrenoceptors stimulates adenylyl cyclase by activating the stimulatory G protein, Gs, which leads to the dissociation of its alpha subunit charged with GTP. This alpha subunit directly activates adenylyl cyclase, resulting in an increased rate of synthesis of cAMP. These catalytic units also phosphorylate the cAMP response element binding protein (CREB), which modifies gene expression. beta1-adrenergic receptors cause actions in the heart in the following manner:Heart SA node: increase in heart rate.Heart AV node: increase in automaticity and conduction velocityHeart Atria and Ventricles: increase in contractility and conduction velocity
9 Activation of adenylyl cyclase by agonists that bind to beta2-adrenergic receptors. Binding to beta2-adrenoceptors stimulates adenylyl cyclase by activating the stimulatory G protein, Gs, which leads to the dissociation of its alpha subunit charged with GTP. This alpha subunit directly activates adenylyl cyclase, resulting in an increased rate of synthesis of cAMP. These catalytic units also phosphorylate the cAMP response element binding protein (CREB), which modifies gene expression. beta2-adrenergic receptors cause relaxation or dilation of smooth muscle in the following organs:Eye: ciliary muscle relaxation (mydriasis - dilation)Arterioles: (coronary, skeletal muscle, pulmonary, abdominal, and renal) dilationLungs: tracheal and bronchial smooth muscle dilationStomach and Intestine: decrease motilityBladder: detrusor muscle relaxationSex Organs, Female: relaxation.
19 STRUTTURA DELLE PRINCIPALI AMINE SIMPATICOMIMETICHE AD AZIONE INDIRETTA
20 Fig. 1. Model of the actions of cocaine and amphetamine at dopamine (DA)-containing nerve terminals. Cocaine blocks the DA transporter (DAT) and therefore DA released physiologically accumulates extracellularly. Amphetamine activity involves several crucial steps [28, 29 and 30]: entry into the neuron by DAT and diffusion; entry into vesicles via vesicular monoamine transporter 2 (VMAT2) and by diffusion; disruption of the vesicular pH gradient and redistribution of vesicular stores of DA into the cytoplasm; and amphetamine-dependent reversal of DAT, which results in massive outflow of DA to the extracellular space via reverse transport. Additionally, amphetamine inhibits monoamine oxidase (MAO) and so decreases the intracellular metabolism of DA. Although the rate-limiting step in amphetamine activity appears to be the displacement of DA from vesicular stores, DAT is required for the release of DA into the extracellular space .Monoamine transporter pharmacology and mutant mice, Trends in Pharmacological Sciences, Volume 23, Issue 8, 1 August 2002, Pages Raul R. Gainetdinov, Tatyana D. Sotnikova and Marc G. Caron