Adrenergic and NANC Receptors Lecture PDF

Overview Adrenergic receptors: Definition, Catecholamines, α and β receptors Non-Adrenergic Non-cholinergic receptors: Definition, GABA, 5-HT, dopamine, purines and pharmacological effects Adrenergic receptors Adrenergic receptor signalling Occurs in the sympathetic nervous system, the C...

Overview Adrenergic receptors: Definition, Catecholamines, α and β receptors Non-Adrenergic Non-cholinergic receptors: Definition, GABA, 5-HT, dopamine, purines and pharmacological effects Adrenergic receptors Adrenergic receptor signalling Occurs in the sympathetic nervous system, the CNS and ‘systemically’ (i.e. direct release into bloodstream → direct innervation of tissues expressing adrenergic receptors). Adrenergic signalling is mediated through the catecholamines noradrenaline and adrenaline. Mediates diverse physiological actions. Unlike AChR associated drugs, drugs that target adrenergic receptors are routinely used clinically. Adrenergic receptors The ANS (Structure) ANS Para- sympathetic Sympathetic Homeo- GANGLIA stasis Adrenergic receptors Neurotransmitters and the ANS Sympathetic Parasympathetic Somatic Spinal cord Preganglionic ACh neuron nAChR ACh nAChR Postganglionic ACh ACh NA neuron Tissue Adrenergic Muscarinic Nicotinic receptor Adrenergic receptors Catecholamine synthesis Catecholamines: Noradrenaline and adrenaline (a.k.a. norepinephrine and epinephrine). Also includes: dopamine. Synthesis: same process as ACh → synthesised → stored in vesicles → released into synaptic cleft, but also produced by the adrenal gland → circulatory hormone → direct adrenergic stimulation of tissue. Catecholamines are synthesised by sequential modifications of the amino acid, TYROSINE. O OH NH2 HO  Adrenergic receptors Catecholamine synthesis O OH L-tyrosine NH2 HO Tyrosine hydroxylase L-DOPA (3,4,-dihydroxyphenylalanine) Amine DOPA decarboxylase Catechol Dopamine Dopamine-β-hydroxylase Noradrenaline Phenylethanolamine-N- Methyltransferase (PNMT) [in adrenal gland] Adrenaline Adrenergic receptors Catecholamine synthesis L-tyrosine Tyrosine hydroxylase L-DOPA Occurs in cytoplasm (3,4,- dihydroxyphenylalanine) DOPA decarboxylase Dopamine NA synthesis occurs Dopamine-β-hydroxylase in sympathetic nerve endings Noradrenaline Phenylethanolamine-N- Methyltransferase (PNMT) Adrenal Gland! Adrenaline Adrenergic receptors Catecholamine synthesis NA synthesis occurs at sympathetic nerve endings BUT ADR synthesis occurs primarily in the chromaffin cells of the adrenal medulla (regulated by cortisol).  PNMT therefore is predominantly expressed in chromaffin cells, conversion of NA  ADR (occurs in cytoplasm).  Both NA and ADR are secreted from the adrenal gland and circulate through the blood stream.  Adrenergic receptors Adrenal gland Various “stresses" stimulate secretion, e.g. exercise, hypoglycaemia and trauma. Following secretion into blood, NA/ADR bind loosely and are carried in the circulatory system by albumin (and other serum proteins).  Adrenergic receptors Catecholamine synthesis – sympathetic nerve endings Like ACh uptake into synaptic vesicles (vAChT), DOPAMINE is taken up into vesicles by the VESICULAR MONOAMINE TRANSPORTER (VMAT) Dopamine Dopamine VMAT Dopamine Dopamine DβH DopaH+ Dopamine mine H+ H+ H+ H+ NA Vesicle Conversion of Dopamine Noradrenaline occurs in vesicle  Vesicular monoamine transporter (VMAT) inhibitors: Reserpine (in the past, used as an antipsychotic and antihypertensive) and Tetrabenazine (hyperkinetic disorders, eg Huntington’s disease). N.B. these drugs effect dopaminergic, adrenergic (and serotonergic) transmission too Why? RESERPINE TETRABENAZINE VMAT METHAMPHETAMINE Dopamine H+ Dopa N H mine H+ H+ Vesicle  Terminating the signal - catecholamine reuptake and metabolism Once a catecholamine molecule has exerted its effect post-synaptically, the response is terminated by one of three ways: 1. Reuptake into the presynaptic neuron. Active processes that require specific proteins = drug targets 2. Metabolism of the molecule ( inactive metabolite). 3. Diffusion away from the synaptic cleft. Catecholamine reuptake and metabolism Reuptake of catecholamines into neuronal cytoplasm is mediated by selective transporters E.g. Noradrenaline transporter (NAT/NET) – sometimes called Uptake 1. - This is the main form of catecholamine clearance (90%). Once back in the neuronal cytoplasm, catecholamines can be recycled back into vesicles (VMAT) or broken down by Either: monoamine oxidase (MAO) Or: catechol-O-methyl transferase (COMT) Adrenergic receptors Catecholamine reuptake and metabolism Monoamine Oxidase  BREAKS DOWN MONOAMINES NAT/NET VMAT (UPTAKE 1) V Inhibition potentiates adrenergic neurotransmission Methamphetamine Cocaine INHIBITS ADRENERGIC TRANSMISSION Tricyclic antidepressants Reserpine, Tetrabenazine  Monoamine oxidase Found on the outer membrane of mitochondria. Two types: MAO-A and MAO-B (show specificity towards various monoamines). Catecholamines (monoamines) normally broken down by MAO-A. Excellent drug target for the control of neurotransmitters concentrations (e.g. In depression). Monoamine oxidase inhibitors (MAOI) Non-selective: phenelzine, iproniazid. - Antidepressants Selective: clorgyline (A), selegiline (B). Not necessarily the first-line treatment for depression anymore because of “cheese syndrome” Foods containing tyramine  excessive tyramine levels due to MAOI. Can cause release of catecholamines from synaptic vesicles, which results in large concentrations in the cytoplasm of the synapse, reversing the flow of NAT and causing mass release of NA  hypertensive crisis HO Tyramine NH2 Adrenergic receptors Types 2 classes: α and β adrenoceptors. All are G-protein coupled receptors! Diversity between receptor family gives rise to many functions. https://www.guidetopharmacology.org/GRAC/FamilyIntroductionForward?familyId=4 Adrenergic receptors Functions RECEPTOR SIGNALLING TISSUE EFFECTS SUBTYPE MEDIATORS Vascular smooth muscle (SM) Contraction Genitourinary SM Contraction α1 Gq / Gi Intestinal SM Relaxation Heart ↑ Excitability Liver Alters glucose levels Pancreatic β-cells ↓ Insulin secretion α2 Gi Platelets Aggregation Nerve endings ↓ NA release Vascular SM Contraction Increase heart β1 Gs Heart rate/contractility Kidney Renin secretion Smooth muscle (eg bronchioles) Relaxation β2 Gs Liver Alters glucose levels Skeletal muscle K+ uptake β3 Gs Adipose Lipolysis Adrenergic receptors α1 adrenoceptors Normally Gq associated (PLC). Downstream targets include: L-type Ca2+ channels, K+ channels, MAPKs and PI3K. Hence α1 signalling can be extremely complex. The variation in the α1 receptor subfamily is linked to the activation of specific, downstream pathways. Adrenergic receptors α1 adrenoceptors Principle function is vasoconstriction. Leads to vascular smooth muscle contraction → mediate increases in peripheral vascular resistance (i.e. Increase blood pressure). Useful for the control of hypertension? Adrenergic receptors α2 adrenoceptors Principle function is decrease adrenergic neurotransmission. How? 1. Gi – ↓ cAMP. 2. Activation of GIRK channels ( membrane hyperpolarisation). 3. Inhibition of neuronal Ca2+ channels. Presynaptic a2 receptors - part of “feedback mechanism” to control NT release. https://www.uky.edu/~mtp/OBI836AR.html Adrenergic receptors β adrenoceptors All are Gs-coupled GPCRs (↑ AC, ↑cAMP). Common downstream effector is PKA. https://www.researchgate.net/figure/Mechanism-of-signal-transduction-from-b-adrenergic-receptors-bAR-The-b-adrenergic_fig3_258995241 Adrenergic receptors β1 adrenoceptors Mostly located in heart and kidney (juxtaglomerular cells  renin release). Cardiac β1 adrenoceptors cause increased: INOTROPY (force of contraction) CHRONOTROPY (heart rate) EFFECT MECHANISM Phosphorylation of Ca2+ channels  influx of Ca2+  POSITIVE INOTROPY contraction of heart muscle POSITIVE Increase in the rate of phase 4 depolarisation of CHRONOTROPY sinoatrial node pacemaker cells Adrenergic receptors β2 adrenoceptors Expressed on SMOOTH MUSCLE (bronchioles, uterus), liver (hepatocytes) and skeletal muscle. In smooth muscle: Gs  AC  cAMP  PKA  phosphorylation of contractile proteins (inhibition)  RELAXATION. In hepatocytes: β2 stimulation  intracellular phosphorylation cascade  activation of glycogen phosphorylase  GLYCOGEN CATABOLISM  ↑ GLUCOSE. Adrenergic receptors β3 adrenoceptors Discovered in 1980s Specifically expressed in ADIPOSE tissue. Stimulation leads to increased lipolysis: breakdown of lipids to triglycerides: β3  AC  cAMP  PKA  activation of lipases. Is β3 a useful target for obesity? Adrenergic receptors Adrenoceptor signalling summary α1 α2 β Gq Gi Gs PLC AC IP3 cAMP Ca2+ Ca 2+ Heart muscle Inhibition Smooth muscle contraction contraction, of NT (vasoconstriction) Smooth muscle release relaxation Adrenergic receptors Pharmacology Summary of drugs which affect adrenergic neurotransmission (which are not receptor agonists / antagonists) DRUG TYPE Example MECHANISM Vesicular Monoamine Reserpine, Inhibition of neurotransmitter Transporter inhibitors tetrabenazine, uptake into synaptic vesicles (VMAT inhibitors) methamphetamine Noradrenaline transporter Cocaine, Inhibition of neurotransmitter (Uptake 1) inhibitors (NET tricyclic reuptake into pre-synaptic neuron inhibitors) antidepressants Monoamine Oxidase Phenelzine, Inhibition of cytoplasmic inhibitors (MAOI) iproniazid breakdown of catecholamines Pharmacology and diseases Adrenoceptor drugs Adrenoreceptor agonists/antagonists are used to influence: Vascular tone Smooth muscle tone Cardiac contractility Mainstay therapies for: Hypertension Asthma Ischemic heart disease Heart failure Pharmacology and diseases α adrenoceptor agonists α1 selective agonists increase peripheral vascular resistance (vasoconstriction): maintain or elevate blood pressure (vasopressor). DRUG CLINICAL APPLICATION Methoxamine Hypotension Nasal congestion Phenylephrine (not taken orally - PE has low (SUDAFED®) bioavailability) Pharmacology and diseases α adrenoceptor agonists α2 selective agonists: Decrease blood pressure by acting in brainstem vasomotor centres to suppress sympathetic outflow to the periphery. DRUG CLINICAL APPLICATION Clonidine: Hypertension, cancer Clonidine pain, opioid withdrawal. Dexmedetomidine Dex: sedation of surgical Guanabenz patients. Pharmacology and diseases α adrenoceptor antagonists More useful than the agonists (many diseases associated with α adrenoceptor “over-activity”). Generally, they cause: Vasodilation Decrease blood pressure (decrease peripheral resistance) Pharmacology and diseases α adrenoceptor antagonists Drug Selectivity Effect Treatment of hypertension associated with Phentolamine Non-selective pheochromocytoma (i.e. not used often) Prazosin α1 > α2 (1000 fold) Lowers blood pressure Terazosin Causes increased release of NA (α2 presynaptic Yohimbine α2 receptors): has been used for erectile dysfunction! Pharmacology and diseases β adrenoceptor drugs All β adrenoceptor drugs tend to end in (L)OL. Can be selective or non-selective. β1 receptors increase: inotropy and chronotopy  increase cardiac output. β2 receptors causes: RELAXATION of smooth muscle: e.g. bronchial, vascular, uterine, and GIT smooth muscle. Pharmacology and diseases β adrenoceptor agonists Used to treat asthma and cardiovascular diseases. Some are non-selective so have multiple effects, e.g. Isoprenaline: lowers peripheral blood pressure, increases cardiac output (β1 receptors are inotropic and chronotropic). Pharmacology and diseases β adrenoceptor agonists DRUG USE b1: Dobutamine Cardiogenic shock / heart failure b2: Metaproterenol Asthma Terbutaline Salbutamol (Ventolin®) Salmeterol (Seretide®) Pharmacology and diseases β adrenoceptor antagonists Sometimes referred to as beta-blockers. Heart β1 receptors are inotropic and chronotropic:  blockade causes ↓ heart rate and myocardial contraction  decreases blood pressure in hypertensive patients BUT: (non-selective beta blockers) can cause life-threatening bronchoconstriction in patients with asthma. Pharmacology and diseases β adrenoceptor antagonists DRUG SELECTIVITY USE Propanolol (Inderal®) Penbutolol Non-selective Timolol Nadolol Hypertension; angina; atrial fibrillation Atenolol (Tenormin®) β1 selective Summary The effects of adrenoceptor signalling are well characterised and far reaching. Inhibition can either occur at the neurotransmitter level (secretion, production etc.) or the receptor level. Their functions make them excellent drug targets for many diseases (e.g. asthma, heart disease, hypertension, hypotension). Like the cholinergic receptors, they are not without their side effects and have many contraindications. Non-adrenergic and Non- cholinergic receptors (NANC Receptors) NANC Receptors Different neurotransmitters So far, we have looked at two, key neurotransmitters: Acetylcholine and Noradrenaline Whilst extremely important modulators of neurotransmission, they are not the only neurotransmitters used. These other neurotransmitters are often referred to as NANC neurotransmitters. NANC Receptors Different neurotransmitters Neurotransmitter Type Location Function Postganglionic sympathetic neurons Fast depolarization/contraction ATP purine (e.g. in blood vessels & vas deferens) (vasoconstriction) GABA Amino acid CNS/ENS Neuronal inhibition/Peristalsis 5-HT monoamine CNS/ENS Neuronal transmission/Peristalsis Dopamine catecholamine CNS / SNS (e.g. kidney) Vasodilation Erection NO gas Pelvic nerves & gastric nerves Gastric emptying vasodilation Enhance vasoconstrictor action of Postganglionic sympathetic neurons NPY peptide (e.g. blood vessels) noradrenaline Noradrenaline release inhibitor Vasodilation Parasympathetic nerves to salivary glands VIP peptide Airway smooth muscle Acetylcholine cotransmitter Bronchodilation Slow depolarization GnRH peptide Sympathetic ganglia Acetylcholine cotransmitter Sympathetic ganglia Slow depolarization Substance P peptide ENS Acetylcholine cotransmitter Vasodilation CGRP peptide Non-myelinated sensory neurons Increase vascular permeability Neurogenic inflammation NANC Receptors Like AChRs, most of the NANC receptors are either ionotropic (ion channel) or metabotropic (GPCR) receptors  METABOTROPIC NANC Receptors IONOTROPIC Types 5-HT1,2, 4-7 5-HT 5-HT3 GABAA GABA NANC GABAB receptors P1 and P2Y receptors ATP (purine) P2X receptor Dopamine D1-5 receptors GABA receptors GABA: γ-aminobutyric acid (produced from glutamate). The main INHIBITORY neurotransmitter in mammalian CNS. Regulates neuronal excitability: causes hyperpolarisation of neurons through the influx of Cl- ions (neuron becomes negatively charged and cannot fire again). How? GABAA receptor is a ligand-gated, chloride ion channel O H2N OH GABA Drugs effecting GABAergic neurotransmission Two type of receptor: GABAA (ion channel) and GABAB (GPCR) Variety of drugs, majority act on GABAA. Used for: sedation, anxiety, control of epilepsy (anticonvulsant). Include: 1. Barbiturates (e.g. pentobarbital – sedative/anxiolytic, but largely replaced by BDZs). 2. Benzodiazepines (BDZs) (major drug type, anxiolytic – e.g. diazepam: Valium®). 3. Ethanol (one of many targets for ethanol, increases GABAA- mediated Cl- influx). Benzodiazepines (BDZs) Augment (heighten) GABA signalling. “Allosteric modulators”. Bind to GABAA receptor, cause positive allosteric modulation ( “PAM”), hence requires presence of GABA 5-HT 5-HT: 5-hydroxytryptamine (SEROTONIN) = MONOAMINE synthesised from tryptophan in serotonergic neurons. Very similar neurotransmission to the catecholamines (NOR, ADR, Dopamine): 1. Uptake into synaptic vesicles (VMAT). 2. Pre-synaptic reuptake mechanisms. 3. Breakdown by MAO. 4. Presence of pre-synaptic, inhibitory “autoreceptors”. 5-HT receptors (Function) Many functions throughout mammalian organisms: Pain Cognitive Mood Motivation/reward perception processing Other physiological Sleep-wake functions e.g. Neuroendocrine function cycle vasoconstriction, GIT motility  For information only – you don’t 5-HT receptors (Subclasses) need to remember all this! RECEPTOR TYPE MECHANISM RESPONSE 5-HT1 Gi/Go ↓ cAMP Inhibitory 5-HT2 Gq ↑ IP3 and DAG Excitatory 5-HT3 Ligand-gated Na+ and Depolarizing plasma Excitatory K+ channel membrane 5-HT4 Gs ↑ cAMP Excitatory 5-HT5 Gi/Go ↓ cAMP Inhibitory 5-HT6 Gs ↑ cAMP Excitatory 5-HT7 Gs ↑ cAMP Excitatory Drugs effecting serotonergic transmission Due to the variety of behavioural and psychological processes regulated by 5-HT, many drugs target 5-HT receptors. Like adrenergic drugs, modulation can either occur at the neurotransmitter level (secretion, production etc.) or the receptor level. NANC Receptors Inhibition of serotonergic transmission Monoamine Oxidase  BREAKDOWN MONOAMINES MAOI SERT = SERT serotonin VMAT (UPTAKE 1) transporter V Tricyclic antidepressants (non-selective reuptake inhibitors) SSRIs (Selective serotonin reuptake inhibitors) Reserpine, Tetrabenazine Methamphetamine NANC Receptors Drugs affecting serotoninergic transmission Mostly used to treat depression. Selective uptake inhibitors (anti-depressants:(SSRIs) – e.g. fluoxetine. Non-selective uptake inhibitors – e.g. TCA like amitriptyline (also inhibit NA reuptake). NANC Receptors Drugs affecting serotoninergic transmission 5-HT3 receptor antagonists can be used as “antiemetics” (eliminates nausea/vomiting). Dolasetron, Granisetron, Ondansetron. - useful in cancer chemotherapy Dopamine receptors Dopamine: another CATECHOLAMINE There are 5 DA receptors: D1 – D5 Two types of dopamine receptor (both GPCRs): D1-like receptors and D2-like receptors. D1-like receptors: coupled to Gs (D1, D5) D2-like receptors: coupled to Gi (D2-4) NANC Receptors Dopamine receptors (Function) Dopamine receptors are predominantly expressed in the CNS. Involved in: Motivation Pleasure Memory Fine motor control Cognitive processing Neuroendocrine function Abnormal dopaminergic function is implicated in several neuropsychiatric disorders e.g. Parkinson’s Disease, schizophrenia. NANC Receptors Dopaminergic drugs used clinically Mostly related to the treatment of either Parkinson’s Disease or schizophrenia. Levodopa (L-DOPA): precursor to dopamine (cannot use DA as it doesn’t cross the BBB)  elevates dopaminergic signalling. O HO OH NH2 HO Selegiline (MAOI) also used. Antipsychotics (for schizophrenia): mostly through antagonism of D2 receptor, but mechanism is complex e.g. Clozapine, Risperidone. NANC Receptors Purine receptors (purinoceptors) ATP ADP AMP NANC Receptors Purine receptors (purinoceptors) Primary role of ATP relates to energy, but it can also act as an excitatory neurotransmitter via purinoceptors: RECEPTOR TYPE LIGANDS P1 GPCR Adenosine Nucleotides (e.g. ATP, ADP, P2Y GPCR UTP, UDP) Ligand gated ion P2X ATP channel Functions of purinoceptors are poorly understood. NANC Receptors Purine receptors (Functions) Functions: poorly understood and still being discovered but include: Vascular endothelial cell-mediated Nociception vasodilation Platelet aggregation Exocrine and endocrine secretion Release of ATP from cells occurs after cell death, but can also take place actively. Few uses clinically, but purinoceptor antagonists of P2Y are used as antiplatelet agents which inhibit blood clot formation e.g. Clopidogrel. Summary Although ACh and NOR are major players in controlling neurotransmission, NANC receptors also play an extremely important role. NANC receptors play pivotal roles in the CNS, thus lend themselves as targets for neurological disorders.