05-BPS337_Sympatho-mimetics-lytics_2024 Lecture Notes PDF

Finish introduction to GPCR function 1  GPCR-more detail And there are 3 types of Gα: Gα s Gα i Gα q G βγ G αι...

Finish introduction to GPCR function 1  GPCR-more detail And there are 3 types of Gα: Gα s Gα i Gα q G βγ G αι GDP 2 G protein Example of a Cellular subunit Effector Molecule Gαs Stimulation of adenylate cyclase (Gαs) Gαi or Inhibition of adenylate Gαo cyclase (Gα). Activation of K (Gi/o) channels (Gβγ). Inhibition of voltage-activated Ca channels (Gβγ). Gαq Stimulation of phospholipase C (Gαq). 3  GPCR Pathways (Gαi, Gαs, Gαq) Ac Norepinephri Ac h M2- ne β-adrenergic h M3- mAChR R Gβ mAChR Gα Gβ Gα γ PIP2 Gα Gβ G γ G G γ T T T i s P q P P + Adenyl Adenyl yl + yl Phospholipase K+ C cyclase cyclase chann el + cAM cAM Diacylglycer IP P Ca 2+ P ol 3 chann el + Protein Protein Protein Ca2+ kinase kinase Kinase releas A A C e + Altered protein Decreased PKA- Increased PKA- phosphorylation & mediated protein mediated protein Activation of calcium- phosphorylation phosphorylation binding proteins 4  Different GPCRs preferentially couple to different G proteins G s β-adrenergic receptors: Gs M2-muscarinic G acetylcholine receptor: i Gi M3-muscarinic acetylcholine receptor: G Gq q 5 6  Adrenergic Receptors-examples Gs and Gi Watch outside of class https://www.nonstopneuron.com/post/alpha-and- beta-adrenergic-receptors  Gq protein pathway Phospholipase C - IP3, DAG Pathway Watch outside of class https://www.nonstopneuron.com/post/ phospholipase-c-ip3-dag-pathway-of-intracellular- signaling 8 Drugs altering the Sympathetic autonomic peripheral nervous system: Sympatho-mimetics and Sympatho-lytics BPS 337 Dr. Roberta King 9 All the potential actions of adrenergic receptors (AR ) 10 Figure 1 GPCRs’ main cell localization. GPCRs are represented as orange proteins with carboxyl groups shown as gray dots and N-terminal groups with symbols of different colors, blue, green, red. Canonically functional GPCRs localize at the plasma membrane level (“1”), but they can also be functional on the membrane of different intracellular compartments: endosomes where their carboxyl domains face the cytosol (“2”); the Golgi apparatus, where they constitute a pre-existing receptor pool and to where they are delivered after being assembled in the perinuclear endoplasmic reticulum (“3”, “4”, respectively); the nucleolus, on the outer and inner nuclear membrane where the GPCR carboxyl domains face the cytosol or the nucleoplasm, respectively (“5”, “6”). GPCRs can also form pre- existing pools in the nuclear inner membrane with their carboxyl domain facing the nucleoplasm (“7”). Finally, GPCRs can be found 11 in the mitochondrial outer membrane where their GPCR carboxyl domains face the intermembrane space (“8”). Sympathetic Division Sympathetic NS Part of the Autonomic (Visceral) NS, which is part of Peripheral NS Stimulation causes “Fight and Flight” characteristics- 12  Sympathetic NS Neurotransmitters are – NE, Norepinephrine (noradrenaline, old name) – EPI, Epinephrine (adrenaline, old name) – D, DA, Dopamine Receptors are Adrenergic – Alpha: a1, a2, – Beta: b1, b2, b3, – Dopamine: D1 – These receptors are also in the CNS so their drugs can have CNS-type side effects But our main purpose here is to discuss the PNS effects 13  Drug mechanism categories Sympatho-mimetics Sympatho-lytics Mimic the agonist action Prevent or lower the agonist-like action Stimulate the receptors Lessen the stimulation of the receptors Agonists Antagonists – And Partial agonists – Competitive or allosteric NT release stimulants NT release inhibitors NT synthesis stimulants NT synthesis inhibitors NT degradation inhibitor NT degradation stimulants NT reuptake inhibitors NT storage prevention 14  Ways to Modify the Autonomic Nervous System and Synaptic Transmission (neurotransmission) Mimetic pathways are the ones labeled AGO (for agonist) Lytic pathways are the ones labeled ANT (for antagonist) 15 R Carlson, Foundations of Behavioral Neuroscience, 9 th edition, 2014 Most important characteristics of the adrenergic receptors (alpha’s) G Second Location, Effector Major action of Type Protei Messen Tissue agonist n ger Most vascular smooth ↑ Ca2+, causes muscle contraction (↑ Alpha1 (α ↑ IP3, Glands vascular resistance) 1) Gq DAG Causes secretion Pupillary dilator Contracts (mydriasis) muscle Pilomotor smooth Contracts (erects hair) muscle Bladder trigone, Contraction prostatic smooth muscle Liver Stimulates glycogenolysis Adrenergic and ↓ Transmitter release cholinergic nerve terminals Alpha2 (α Causes contraction ) 2Trevor’s GiExamination Table information from Katzung & Pharmacology: ↓ cAMP & Smooth muscle Board Review, 13 edition. Tables 6-2 and 9-1. Modified and combined by Dr. King Platelets Stimulates aggregation 16 Most important characteristics of the adrenergic receptors (beta’s) G Second Location, Major action of Type Protei Messeng Effector Tissue agonist n er Heart-sino-atrial Beta1 ( node ↑ Heart rate, β 1) Gs ↑ cAMP ventricles ↑ force; Juxtaglomerular ↑ Renin release cells of kidney Beta2 ( Airways, uterine, and vascular Relaxes β 2) Gs ↑ cAMP smooth muscle Liver (human) ↑ Glycogenolysis Pancreatic β (B) ↑ Insulin release cells Somatic motor neuron terminals Causes tremor (voluntary muscle) ↑ Heart rate, ↑ Heart Table information from Katzung & Trevor’s Pharmacology: Examination & Board Review, 13 edition. Tables 6-2 and 9-1. Modified and combined force; 17 by Dr. King  Most important characteristics of the adrenergic receptors (dopamine’s) G Second Location, Major action Type Protei Messenger Effector Tissue of agonist n Dopamine1 Renal and other Dilates (D1) splanchnic (↓ resistance) Gs ↑ cAMP blood vessels Dopamine2 Inhibits (D2) Gi ↓ cAMP Nerve terminals adenylyl cyclase Table information from Katzung & Trevor’s Pharmacology: Examination & Board Review, 13 edition. Tables 6-2 and 9-1. 18 Modified and combined by Dr. King 19 Chemistry and receptor selectivity 20 Functional groups leading to selectivity 21 Example of formoterol binding to B2 22 Albuterol 23 24 25 Recently proven, Not orally effective as decongestant 26 27  Extra slides 28 29 30  Termination of action of NE and analogs Epinephrine, norepinephrine, dopamine – Rapidly metabolized in the synapse to inactive products COMT, catechol-O-methyl transferase MAO, monoamine oxidase – Also inactive orally because same in GI and liver. (parenteral, topical only) 31  Summary-mechanisms of action synthesis, storage, release, receptor interactions, and termination of action of the neurotransmitters all contribute to the action of autonomic drugs (Figure 6–2). 32 Summary-mechanisms of action synthesis, storage, release, receptor interactions, and termination of action of the neurotransmitters all contribute to the action of autonomic drugs (Figure 6–2). 33 34  Extra slides 35 Functional groups leading to selectivity 36 37  Most important characteristics of the adrenergic receptors G Location, effector Second Major Functions Receptor tissues Protei Messenger of agonists n ↑ Ca2+, causes smooth muscle, Alpha1 (α1) glands Gq ↑ IP3, DAG contraction, secretion ↓ Transmitter Nerve endings, release (nerves), Alpha2 (α2) some smooth Gi ↓ cAMP causes contraction muscle (muscle) Cardiac muscle, ↑ Heart rate, ↑ renal Beta1 (β1) juxtaglomerular Gs ↑ cAMP force; ↑ renin release apparatus Relax smooth Smooth muscle, muscle; ↑ Beta2 (β2) liver, Gs ↑ cAMP glycogenolysis; heart ↑ heart rate, force Beta3 (β3) Adipose cells Gs ↑ cAMP ↑ Lipolysis Dopamine1 Relax renal Smooth muscle Gs ↑ cAMP vascular smooth 38  Example of Gs-Coupled Signal Transduction Pathway: β1-Adrenergic Receptor–Mediated Increase in Cardiac Contractility 39