Neurochemistry and neuroendo Flashcards
(32 cards)
G Protein receptors
► Class 2
► Trans-membrane protein: all span the cell membrane seven times (serpentine receptors).
► Cyclise mediated second messenger activation (GTP, ATP etc)
► Gs-proteins are stimulatory; Gi-proteins are inhibitory to the adenylate cyclase
► Third variant acts via phospholipase C
► e.g. DA receptors, most 5HT except 3, NEN and neuropeptides including opioid receptors are G coupled.
Dopamine receptors D1-D5
D1 - 5 : All G protein coupled
D1-like D1 & D 5; increase adenylate cyclase (stimulatory)
D1 exclusively postsynaptic; resistant to antagonism
D5 more limbic in distribution; 10times higher dopamine affinity
D2,3& 4 ; decrease adenylate cyclase (inhibitory)
D4 primarily - frontal cortex and clozapine high affinity.
D4-selective antagonists do NOantipsychotic efficacy.
Kapur 2003 proposal about dopamine and mesolimbic function
Clinical relevance: Kapur proposed that in the normal individual, the role of mesolimbic dopamine is to attach significance or ‘salience’ to an external stimulus, or an internal thought,. This converts a neutral piece of information into an attention grabbing information (Kapur, 2003).
Noradrenaline receptors alpha and beta:
α1 phospholipase C coupled; mostly postsynaptic
α2 Gi coupled ; mostly presynaptic autoreceptors
β-Gs coupled; predominate locus ceruleus – may regulate α
β1-receptors – high affinity to norepinephrine
β2-receptors – high affinity to epinephrine
Locolisation of serotonin
Most serotonin is in periphery (gut, platelets) but cannot cross BBB.
Median and the dorsal raphe nuclei; widespread cortical projection; also spinal cord
location/types of following receptors:
5HT1A
5HT1B
5HT1D
5HT2
5-HT1A receptors – Gi coupled postsynaptic; Antidepressant response; sexual behaviour
5-HT1B receptors – Gi coupled presynaptic;
5-HT1D receptors – Gi coupled -pre and postsynaptic.
5-HT2 receptors - phospholipase C coupled; postsynaptic; antagonism leads to antipsychotic response (atypicals) and sedation;
LSD causes 5-HT2 stimulation;
down regulation after AD/ ECT.
5-HT6 may be involved in antidepressant action
DOPA decarboxylase (DDC) function
synthesizing 2 important neurotransmitters, dopamine and serotonin
Following the hydroxylation of tyrosine to form L-dihydroxyphenylalanine (L-DOPA), catalyzed by tyrosine hydroxylase,
DDC decarboxylates L-DOPA to form dopamine. This
neurotransmitter, particularly abundant in basal ganglia.
Dopamine is also produced by DDC in the sympathetic nervous system and is the precursor of the catecholaminergic hormones, noradrenaline and adrenaline in the adrenal medulla.
In the nervous system, tryptophan hydroxylase produces 5-OH tryptophan,
decarboxylated by DDC, giving rise to serotonin.
DDC is a homodimeric, pyridoxal phosphate-dependent enzyme.
functions of ACH and
localisation
Modulate arousal, attention (muscarinic in CNS) learning, memory, REM sleep pain perception thirst and parasympathetic mediation.
- ascending system of cholinergic neurons originating in
the reticular formation - cholinergic cells in the nucleus basalis of Meynert
Reuptake of GABA
Source: glutamic acid (glutamate)
Synthetic enzymes:
glutamic acid decarboxylase (GAD)
Breakdown enzymes:
GABA transaminase
Breakdown product:
Broken down to glutamate, and then eventually to
succinic acid
Reuptake: reuptake into both presynaptic nerve terminals and surrounding glial cells; uptake system is bidirectional and both temperature- and ion-dependent process; (inhibited by tiagabine)
Function: Mediates anxiety, seizure cessation, and actions of benzodiazepines, barbiturates, and alcohol.
source of glutamate
functions of glutamate
- from 2-oxoglutarate and aspartate by aspartate
aminotransferase, - from glutamine by glutaminase, or
- from 2-oxoglutarate by ornithine aminotransferase
Important metabolic role – intermediary in oxidation
pathway (malate shuttle),
immediate precursor of all GABA in CNS,
intermediary in ammonia cycle;
NMDA - memory acquisition, developmental plasticity, epilepsy, ischemic brain injury. NMDA mediates long term potentiation (LTP = a change in physical properties of neurones and synapeses.e.g. in memory)
excitotoxic glutamate toxicity in stroke/schizophrenia/seizures suspected.
NMDA antagonists can cause hallucinations – e.g. PCP,
ketamine
glutamate receptors
metabotropic - 8 in total; 3 groups.
- mGluR1& mGluR5 – linked to phospholipase C
Ionotropic: NMDA and non-NMDA
- NMDA - made up of subunits with distinct binding
sites for glutamate, glycine, phencyclidine (PCP),
magnesium, and zinc. - Non NMDA – kainate binding or AMPA type.
Glycine function
Synthesized from serine by serine trans-ydroxymethylase
and glycerate dehydrogenase
mandatory adjunctive neurotransmitter for glutamate activity and an independent inhibitory neurotransmitter at
its own receptors
NON strychnine-sensitive glycine receptor= excitatory glycine site on NMDA
strychnine-sensitive glycine receptor= inhibitory, seen in spinal cord. May reduce negative schizo symptoms
Substance P
primary NT in afferent sensory pathways (think PAIN)
also seen in the striatonigral pathway.
reduced levels in huntingtons
Neurotensin (peptide)
coexists with dopamine in some axon terminals.
may benefit psychotic symptoms.
have reward-enhancing effects through its
antidopaminergic actions in the prefrontal cortex
Cholecystokinin
pathophysiologies of
schizophrenia, eating disorders and movement disorders.
CCK infusion induces panic attacks in people with panic disorder. CCK antagonists may have anxiolytic effects.
Somatostatin is
also known as growth hormone-inhibiting factor (released from intestine?)
Neuropeptide Y
has been shown to stimulate the appetite.
It is a 36 aminoacid peptide found in hypothalamus.
?aetiology of obesity where in the loss of negative feedback of Corticotrophin releasing hormone on NP-Y may be a cause for increased cortisol levels
Leptin – it has a key role in regulating energy intake and expenditure: it is produced by adipose tissue in response to fat levels. On fat storage, leptin signals the brain to stop seeking food by inhibiting NPY and AgRP (Agouti-related peptide).
may have role in AP related weight gain
Ghrelin – produced in somach and pancreas: stimulates appeptite
different opiod receptors
Opiate receptors
µ receptor = morphine, opiate alkaloids, β-endorphin, and enkephalins, supra spinal analgesia
δ receptor = enkephalins
κ receptor = dynorphin, spinal analgeisa
σ receptor - naloxone DOES NOT reverse agonist activity. Phencyclidine, haloperidol, and steroids are agonists:
indicate that σ receptors play a role in motor function and possibly drug abuse.
functions of smooth ER
Smooth ER plays different functions depending on the specific cell type including lipid (incl.phospholipid) and steroid hormone synthesis,
breakdown of lipid-soluble toxins in liver cells,
control of calcium release in muscle cell contraction.
Choline acetyl transferase (ChAT)
reduced to a greater extent (85%) in patients with hallucinations in Lewy body dementia than in those without hallucinations (50%).
This is more pronounced in parieto-temporal regions, hippocampus and entorhinal cortex.
As a consequence, brain ACH levels are reduced in DLB similar to Alzheimer’s. This may partially explain the altered sleep-wake patterns seen in DLB and also the response of hallucinations to acetylcholinesterase inhibitors.
Question 9. Which of the following receptors increase adenylate cyclase to stimulate cell machinery? Alpha 1 Beta adrenergic Dopamine D2 Dopamine D3 Dopamine D4
Alpha1 receptors are phospholipase C coupled;
Alpha 2 are Gi coupled(inhibitory).
Beta receptors Gs coupled - so they increase adenylate cyclase.
D2 receptors are also G protein coupled; but unlike the G-coupled D1 family of receptors, the
D2 family inhibits (decreases) adenylate cyclase activity.
distribution of DA receptors
D1 and D2 are predominant in the caudate & putamen, and have wide distribution 1.e. striatum, hypothalmic, mesolimbic
D3-nucleus accumbens,
D4– prefrontal cortex,
D3 +D4: more localised: mesolimbic, cortical and hippocampal).
D5-Hippocampus.
Question 22. Which one among the following is a 5-HT 2a and 5-HT 2b agonist? Bromocriptine Bupropion Clonidine LSD Riluzole
Bromocriptine is a dopamine receptor agonist, which is used to suppress galactorrhoea and postpartum lactation.
Clonidine is a noradrenergic agonist. LSD is a 5-HT 2a and 2b agonist and produces a hallucinogenic effect.
exitatory AAs and receptors
Excitatory amino acids are glutamic acid, asparate and homocysteine.
excitatory amino acid receptors;
N-methyl D aspartate (NMDA),
amino-3 hydroxy 5-methyl 4-isoxazole propionate (AMPA), kainate
Metabotropic (G-protein coupled receptors).
