MD224 Topic 3 Biogenic amines.pdf

Topic 3 Biogenic amines 1 Biogenic amines • Bioactive amine neurotransmitters • Implicated in wide range of behaviours • E.g., movement, reward, addiction, depression, sleep • Drugs that affect their neurotransmission are frequently used in pharmacology 2 The biogenic amines all have an amino...

Topic 3 Biogenic amines 1 Biogenic amines • Bioactive amine neurotransmitters • Implicated in wide range of behaviours • E.g., movement, reward, addiction, depression, sleep • Drugs that affect their neurotransmission are frequently used in pharmacology 2 The biogenic amines all have an amino group 3 Catecholamines Contain a catechol nucleus and an amine group Dopamine Neurotransmitter: Dopamine: Norepinephrine: Epinephrine: Catecholaminergic neuron Dopaminergic neurons Adrenergic neurons Adrenergic neurons 4 The biosynthetic pathway for the catecholamine neurotransmitters Tyrosine DOPA Dopamine They are all derived from tyrosine and are part of the same biosynthetic pathway Norepinephrine Epinephrine 5 Tyrosine hydroxylase: Controls the rate limiting step Only found in sympathetic neurons and adrenal chromaffin cells Diagnostic of a catecholaminergic cell Its expression in a cell is controlled by Nerve Growth Factor and other factors controlling growth and differentiation of sympathetic neurons 6 Tyrosine Precursor of Dopamine DOPA Dopamine Neurotransmitters Norepinephrine Epinephrine and norepinephrine function as both systemic hormones and as neurotransmitters Epinephrine 7 Uptake into and storage in vesicles • Vesicular monoamine transporter (VMAT) • Can transport catecholamines and indoleamines • Inhibited by reserpine • Vesicles in adrenergic neurons and chromaffin cells contain Dopamine β-hydroxylase (DBH) • In adrenal chromaffin cells the vesicles are called chromaffin granules 8 Uptake into and storage in vesicles H+-ATPase • Vesicular monoamine transporter (VMAT) • Can transport catecholamines and indoleamines • Inhibited by reserpine VMAT Synaptic vesicle • Vesicles in adrenergic neurons and chromaffin cells contain Dopamine β-hydroxylase (DBH) • In adrenal chromaffin cells the vesicles are called chromaffin granules 9 Catecholamine receptors Dopamine receptors, D1-D5 are all coupled to G proteins Dopamine Dopamine D1-like receptor D2-like receptor D1-like receptor: • D1 and D5 – activate adenylate cyclase (increases cAMP) D2-like receptor: • D2,3,4 – inhibit adenylate cyclase (decreases cAMP) 10 Inactivation of biogenic amines 1. Reuptake via Dopamine Transporter • Into nerve terminals for reuse or into glial cells • Na+-dependent DA transport protein • Inhibited by cocaine, amphetamines 2. Enzymatic degradation 3. Diffusion out of the synaptic cleft 11 Enzymatic inactivation of dopamine 12 Key degradation enzymes 1. MAO: Monoamine oxidase • MAO enzymes deaminate catecholamines  inactive derivatives • Associated with outer mitochondrial membrane • Work with AD (aldehyde dehydrogenase) 2. COMT: Catechol-O-methyltransferase • Transfers methyl groups to hydroxyl group of catechols • Cytosolic 13 Dopamine system and disease • Parkinson's disease • Attention deficit hyperactivity disorder • Tourette syndrome • Schizophrenia • Bipolar disorder • Addiction 14 Parkinson’s disease Insufficient dopamine in the nigrostriatal pathway Dopaminergic neurons project from the substantia nigra to the striatum 15 Neural projections in motor control Spinal Cord Motor Cortex Other Neurotransmitters Muscle Thalamus GABA Acetylcholine Striatum Globus Pallidus Pars Compacta Dopamine Substantia Nigra 16 Neural projections in motor control Spinal Cord Motor Cortex Other Neurotransmitters Muscle Thalamus GABA Acetylcholine Striatum Globus Pallidus Pars Compacta Dopamine Substantia Nigra Loss of dopamine causes impairment of motor control 17 Parkinson’s disease Normal The pars compacta region of the substantia nigra normally appears dark because dopamine-producing neurons are highly pigmented Parkinson’s disease The loss of pigmentation is due to death of these dopamine-producing neurons 18 Biochemistry of Parkinson’s disease • Familial alterations in Park genes: • Mitochondrial dysfunction • Parkin (Park2), DJ-1 (Park7), PINK (Park6) • Defects in ubiquitin-proteasome system (UPS) • alpha-synuclein (Park1), Parkin, DJ-1 • Sporadic: • Environmental toxins, eg, MPTP, rotenone • Oxidation of dopamine, eg, to 6-hydroxydopamine Oxidative stress Protein aggregation 19 Lewy bodies Normal substantia nigra Pigmented neurons Parkinson’s substantia nigra Loss of pigmented neurons Lewy bodies 20 Tyrosine Tyrosine Sites of action of common treatments for Parkinson’s disease: Increases dopamine levels Dopamine All enhance dopamine signalling MAO-B DA Bind to DA receptors Inactivation Release Stimulates release of DA Inhibits reuptake DA Agonists Selegeline Inhibits MAO-B DA Amantidine Levodopa L-DOPA Reuptake Degradation Binding COMT DA Receptors COMT Inhibitors Block degradation of DA and L-DOPA 21 What we have covered Lecture 1: CNS neurotransmission What is a neurotransmitter? How do neurotransmitters work? How are signals transmitted from one neuron to another? Lecture 2: Acetylcholine and amino acids Acetylcholine signalling What are excitatory and inhibitory neurotransmitters? Ionotropic and metabotropic receptors for ACh and amino acid neurotransmitters Lecture 3: Biogenic amines What are biogenic amines? What role do they play in health and disease? 22 Thank you 23