Reference: Devlin Ch 23 Selective reading! MOHAMAD NUSIER, M.D., Ph.D. Neurotransmitters Reference: Devlin Ch 23 Selective reading! MOHAMAD NUSIER, M.D., Ph.D.

Neurotransmitters Excitatory: Inhibitory: Acetylcholine Chatecholamines Inhibitory: Glycine* (acts in spinal cord & brain stem) GABA* (acts in all other parts of brain) Taurine * Major ones

The biogenic amines: indolamines Serotonin Histamine The amino acid transmitters: Glutamate GABA Glycine

Acetylcholine Synthesized in terminals from acetyl CoA (found everywhere) and choline (from blood and recycled ACh, but not synthesized in neurons) Synthesizing enzyme = CAT (choline acetyl transferase)

Acetylcholine Inactivated = by ACHesterase; ACh is not taken up into neurons Used by somatic motor neurons within CNS Two major subtypes of receptors = nicotinic (nAChR) and muscarinic (mAChR), each of which has its own subtypes

Acetylcholine nAChRs are directly gated channels for Na+ and K+ nAChRs are found on striate muscle (N1), postganglionic neurons (N2); CNS. mAChRs are linked to 2nd messengers mAChRs are found on visceral smooth, cardiac muscle, glands, postganglionic neurons, CNS

Dopamine Is a biogenic amine & specifically a catecholamine, so it shares a pathway with NE & EPI Synthesized from tyrosine (Tyr is from the essential AA Phe) Rate limiting enzyme is tyrosine hydroxylase Carbidopa blocks conversion of DOPA (dihydroxyphenylalanine) to dopamine by dopa decarboxylase, but cannot cross the BBB

Inactivation: reuptake (blocked by cocaine); degradation by COMT (extracellular) and by MAO (intracellular) A major metabolite: HVA (homovanillic acid) which shows up in CSF So far, there are 5 subtypes known, all 2nd messenger-linked DA is important in mood disorders, schizophrenia, basal ganglia function Parkinson's results from loss of DA neurons in basal ganglia

Norepinephrine Shares pathway with other catecholamines (Dopamine) Used in CNS (locus coeruleus and lateral tegmental nuclei of brainstem) and by most post-ganglionic sympathetic neurons

Inactivation = reuptake (blocked by cocaine); degradation by COMT in extracellular space and by MAO (intracellular) At least 4 subtypes, all 2nd messenger-linked. (b1,b2 increase cAMP, a2 decreases cAMP, að1 acts through PLC) Agonists include ephedrine, phenylephrine (a), isoproterenol (b) Antagonists include phentolamine (a), propranolol (b)

Epinephrine A transmitter in a few brain stem neurons an adrenal neurohormone

Synthesis of catecholamines

Serotonin (5HT = 5-hydroxytryptamine) Synthesized from tryptophan Rate-limiting enzyme = tryptophan hydroxylase Inactivation = reuptake into terminals, degradation by MAO The raphe nuclei of the brain stem are the major source of 5HT

raphe nuclei are midline, i.e. unpaired nuclei Many subtypes, many actions Mostly 2nd messenger-gated, but at least one direct channel receptor Many anti-depressants are targeted at 5-HT neurons (the popular prozac)

Histamine A local hormone and a hypothalamic transmitter At least three receptor subtypes known so far Synthesized from histidine

Glutamate Mediates fast excitatory communication in the CNS (direct channel-linked) Acts through three direct ligand-gated channel receptor types: NMDA , AMPA and kainate (KA) receptors, And through two or more types of metabotropic (G-protein linked) receptors (ACPD and L-AP4)

Glutamate NOTE: The names reflect their different pharmacological profiles, but physiologically, in the body, they all bind glutamate NMDA receptor channels admit Ca ++ which can have important 2nd messenger effects GLU is an abundant amino acid in the brain, maybe 30% of which is transmitter Inactivation = reuptake by glia, conversion to glutamine, return to neuron terminal (where it can be reconverted to Glu)

Glutamate Glu is synthesized by 3 methods: Deamination of Glutamine by glutamase Amination of alpha ketoglutarate by Glu dehydrogenase utilizing free ammonia Transamination of alpha ketoglutarate by transaminase

GABA Major inhibitory transmitter in the CNS Altered GABAergic function may play a role in many clinical situations (e.g. basal ganglia disorders, seizure disorders, schizophrenia, sleep disorders) Synthesized from glutamate by GAD (glutamic acid decarboxylase) Inactivation = reuptake by nerve terminals for reuse and by glia, where it undergoes conversion to glutamine, return to neuron terminal (where it can be reconverted to Glu and then to GABA)

GABA At least two major receptor subtypes: GABAA is a direct-gated Cl- channel GABAB is G-protein linked, inhibited by increasing K+ permeability, decreasing Ca++ influx (especially as presynaptic inhibition), decreases cAMP Benzodiazepines (Valium) and, probably, neurosteroids bind to GABAA receptor, increase GABA effect Agonists: Muscimol (A), baclofen (B) Antagonists: Bicuculline (A)

Glycine The other inhibitory transmitter in the CNS Receptor is direct ligand-gated Cl- channel Used by Renshaw cells (inhibitory interneurons in spinal cord, supplying recurrent inhibition) Antagonist = strychnine

GABA and Glycine Most inhibitory neurons use one or the other. Inhibits the ability to fire action potentials. GABA made from glutamate by glutamic acid decarboxylase (GAD), requires Vit B6 as cofactor. B6 deficiency can lead to loss of synaptic transmission. Receptors: GABAa and GABAb Implicated in epilepsy Glycine- about 1/2 of neurons in spinal cord use glycine, receptors similar to GABAa receptors Both GABA and glycine are rapidly taken up by glia and neurons. Hyperglycinemia- defect in glycine uptake and removal leads to severe mental retardation.

Similar to glutamate: excitatory NT Functions in fewer pathways Aspartate Similar to glutamate: excitatory NT Functions in fewer pathways Made from oxaloacetate by tranamination reaction Aspartate can not pass through BBB

Nitric Oxide Effects: vasodilatation, neurotransmission (penile erection), killing tumor cells and parasites Made from arginine by Nitric Oxide synthase NO activates guanylate cyclase: increase cGMP: activates protein kinases Can cross membranes (gas)

Synthesis, Release, and Reuptake of the Inhibitory Neurotransmitters GABA and Glycine Vesicular transporters regulate the amount and type of neurotransmitter sequestered into synaptic vesicles

Synthesis, Release, and Reuptake of the Inhibitory Neurotransmitters GABA and Glycine

Phenylketonuria (PKU) This is one of the most common inborn errors of metabolism which affects cerebral activity, affecting approximately 1 out of 20,000 infants. The defect is a lack of phenylalanine hydroxylase and leads to increased concentrations of phenylalanine. The neurochemical mechanisms involve tyrosine and tryptophan pathways. Fortunately, the disorder can be treated in many cases by diet restriction.

Tay Sachs Disease This is a lipid-storage disorder transmitted as an autosomal recessive trait. The metabolic defect is a deficiency of the hexosaminidase found in lysosomes involved in ganglioside degradation. Its absence causes lipids and proteins to accumulate in membranous cytoplasmic bodies. There is no established therapy, although recent research has searched for a means of enzyme replacement.