BIPN 140 Cellular Neurobiology
Prof. Shelley Halpain
shalpain@ucsd.edu
Lecture 12 “Neuromodulators”
Office hours: after class, or by appt.
Neuromodulators
•Learning objectives:
•Describe some of the features that distinguish fast and slow
neurotransmission
•Know the different classes of neuromodulators and their major receptor
targets
•Recognize the major steps in the synthesis of the biogenic amines, and the
enzymes that catalyze them
•Name the major brain nuclei where the biogenic amines are produced and
some of their major functions in behavior
•Understand the action of certain therapeutic agents and drugs of abuse that
target the DA, NE, and 5HT systems
•Be able to state some examples of neuropeptides and their function
•Understand the mechanism of signal termination for the different
neuromodulators: i.e., reuptake (if any) and degradation
•Cite two examples of ‘unconventional’ neurotransmitters/modulators,
describe their synthesis, mechanism of action, and mode of signal termination
– explain what makes them unconventional
Fast vs. Slow NeuroTransmission
‘Fast’:
•Response times on msec time scale
•Mediated by ACh and the amino acids Glu, glycine, & GABA
•act via ionotropic receptors
•Actions are spatially limited (i.e., typically restricted to a single
synapse)
‘Slow’:
•Response times on tens msec to seconds timescale
•Mediated by neuromodulators (monoamines, neuropeptides,
fatty acid amides, & others
•typically do NOT act via ionotropic receptors – exception:
5HT3! (but note: they do not all act via metabotropic receptors
either)
•Actions can be spatially distant (paracrine effects; note that
many hormones act in slow transmission also)
According to your Neuroscience textbook, all
conventional neurotransmitters that can act in ‘fast’
neurotransmission via ionotropic receptors also can act
in ‘slow’ neurotransmission via metabotropic receptors
… except one
glycine
Is this true??
J Physiol. 2008 June 15; 586(Pt 12): 2913–2926.
Synaptic inhibition by glycine acting at a metabotropic
receptor in tiger salamander retina
Mingli Hou, Lei Duan, and Malcolm M Slaughter
“Glycine is the lone fast neurotransmitter for which a metabotropic
pathway has not been identified. In retina, we found a strychnineinsensitive glycine response in bipolar and ganglion cells. This
glycine response reduced high voltage-activated calcium current. It
was G-protein mediated and protein kinase A dependent.”
.......
“This study resolves the curious absence of a metabotropic glycine
pathway in the nervous system and reveals that the major fast
inhibitory neurotransmitters, GABA and glycine, both activate Gprotein-coupled pathways as well.”
Difference between a neurotransmitter & a
neuromodulator? Essentially none!
Certain “neuromodulators” are commonly referred to as
“neurotransmitters”:
This is typical for the monoamines: serotonin, norepineprine,
dopamine:
Why? Their release is synaptic, ie., they act very locally, and they
are often the the primary or possibly only known ligand at that
synapse
Other neuromodulators, like enkephalins, neuropeptides, etc are
usually NOT called neurotransmitters
Why? They are often NOT the only active ligand at their release
site, and they often act in a more paracrine fashion
Monoamines (catacholamines & serotonin) as targets of
psychiatric therapeutics & drugs of abuse
VMAT
All the biogenic amines (“monoamines”) are synthesized in the
cytosol & then loaded into vesicles via a transporter protein
called VMAT – vesicular monoamine transporter
Catacholamine Synthesis
Dopamine, norepinephrine (noradrenaline),
epinephrine (adrenaline)
• All derived from tyrosine via a stepwise enzymatic pathway
• Step1 – tyrosine hydroxylase – is the
rate-limiting step (creates the
‘catachol’ moeity)
• Synthesis occurs in the cytoplasm of
nerve terminals
• Loaded into synaptic vesicles by
VMAT (vesicular monamine
transporter)
Dopamine
• Essential role in coordinating body movements
• DA neurons in substantia nigra project to striatum and elsewhere
• Loss of SN neurons leads to Parkinson’s disease; treatment by replacing dopamine
via administration of its precursor L-DOPA
• Essential role in motivation and reward, arousal, activity level; emesis
Norepinephrine
CNS: Essential role in sleep and arousal, attention, feeding, emotional state
PNS(autonomic) : sympathetic ganglia of visceral motor system (cardiovascular
function, respiration, digestion, etc)
Reuptake inhibitors like tricyclic
antidepressants (e.g., desipramine)
used to treat depression
All noradrenergic transmission
in the brain comes from one
tiny midbrain nucleus!
Epinephrine
In CNS neurons are found only at lower brain stem levels, project to thalamus &
hypothalmus
Functions remain poorly understood
Termination of Catacholamine Neurotransmission
• DA: taken up into neurons & glia via the dopamine
transporter (DAT) – target of cocaine (which inhibits DAT)
• NE taken up into neurons & glia via the norepinephrine
transporter (NET) – amphetamines block both DAT & NET
Catacholamine actions are further terminated by 2
major enzymes:
Catachol-O-methyl transferase (COMT) – located in
cytoplasm of neurons & glia
Monoamine oxidase (MAO) – located in
mitochondria of neurons & glia
MAO inhibitors are older drugs used to treat
anxiety & depression; more side-effects than newer
medications
Widespread Projections of Histaminergic and
Serotonergic Neurons
Histamine
Synthesized in a single step from histadine
Degraded by combined actions of MAO and histamine methyl transferase
No transporter identified yet
All known receptors are metabotropic
Functions: mediates
arousal, attention,
vestibular system
btw: Allergic reactions are due to
histamine released from mast
cells in the periphery – NOT from
effects in CNS
Serotonin
•
•
•
•
•
Synthesized in 2 steps from tryptophan
Loaded into vesicles by VMAT (i.e., same as for catacholamines)
Degraded mainly by MAO
Taken up by a specific serotonin transporter (SERT)
Most actions are at 5HT1 & 5HT2 metabotropic receptors; but the
5HT3 receptor is a ligand-gated ion channel
Functions: mediates arousal,
attention, emotional state, circadian
rhythms, motor function, appetite
Many psychotropic drugs target 5HT
MAO inhibitors: depression, anxiety
SERT inhibitors (SSRIs): e.g. Prozac,
treat depression
SSRI Antidepressants
The most popular types of antidepressants are
called selective serotonin reuptake inhibitors
(SSRIs). These include:
Fluoxetine (Prozac)
Citalopram (Celexa)
Sertraline (Zoloft)
Paroxetine (Paxil)
Escitalopram (Lexapro).
Prozac Nation?
Depression is no laughing matter…
Major depressive disorder (MDD) (aka: clinical depression,
major depression, unipolar depression, or unipolar disorder)
is a mental disorder characterized by an all-encompassing low
mood accompanied by low self-esteem, and by loss of interest
or pleasure in normally enjoyable activities.
An estimated 8-12% of people will
suffer from depression at some
point during their lives
• Caused by convergence of biological, psychological, social conditions
• 10-20% of cases can resolve without treatment
• Rate of recurrence is high
• Complex, multi-symptom disorder
• Often co-occurs with anxiety disorders, substance abuse
An estimated 26.2 percent of
Americans ages 18 and older
— about one in four adults —
suffer from a diagnosable
mental disorder in a given
year
Major depressive
disorder is the
leading cause of
disability in the U.S.
for ages 15-44
But depression is a highly treatable disorder
http://www.nimh.nih.gov/health/topics/
Monoamines have intersecting functions in emotions, attention, motivation,
etc.
Naturally this is an over-simplification!! Human behavior is complex & neural
circuits are still poorly characterized
ATP & other Purines at Neurotransmitters
All synaptic vesicles
contain ATP; it may be a
“co-transmitter”
Adenosine is released
from neurons & glia,
from but NOT from
vesicles & not in a
calcium-dependent
manner; it is generated
from ATP via
extracellular enzyme
pathways
Purine neurotransmitters
activate specific types of
receptors, called
“purinergic receptors”;
both channels & GPCRs
have been identified
Neuropeptides
Over 100 different peptides, each 3-30 amino acids in length
Synthesis:
Synthesized by translation of genetically encoded mRNAs
Synthesized as a ‘pre-propeptide,’ which contains a signal sequence (targets the
peptide to cross the membrane of the ER
Processed by specific peptidases into the propeptide, in part by removing the
signal sequence
The propeptide is packaged into vesicles after being processed by the Golgi,
then further processed into one or more individual peptides
Most actions are at metabotropic receptors
Signal termination: Degraded mainly by extracellular peptidases
Numerous functions, depending on the amino acid sequence: pituitary, brain/gut,
hypothalamic releasing hormones, opioids
General Classes of Neuropeptides (note:
you do not need to memorize these)
Many Neuropeptides are Generated via Proteolytic Processing from Precursor Proteins
Specific Peptides are Produced in Specific Brain Nuclei
Unconventional Neurotransmitters
i.e., not released from vesicles!
Distribution of cannabinoid receptors
Endocannabinoids (endogenous ligands at cannabinoid receptors)
Synthesized from fatty acids
(note: you do not need to memorize
these structures or enzymes!)
Signal termination: uptake into ‘postsynaptic’
neuron and hydrolyzed by FAAH (fatty acid
amide hydrolase)
Receptors (metabotropic only, so far)
are widely distributed throughout the
brain; CB1 & CB2
Agonists, antagonists, & FAAH
blockers under development
as potential therapeutic
agents (appetite, pain,
depression, glaucoma)
Unconventional Neurotransmitters
Nitric Oxide
Produced by NO synthase, which is stimulated by calcium/calmodulin
Mechanisms of signaling: a) direct activation of a specific type of guanylyl cyclase
b) Nitrosylation of specific proteins
Signal termination mechanism: none needed, because NO is very short-lived – it
quickly decays spontaneously by reacting with O2
Unconventional neurotransmitters/modulators can serve as ‘retrograde signals’
‘conventional’
information
flow
presynaptic
‘synapse’
Retrograde signals
postsynaptic
What are the criteria for designating a compound as a ‘Neurotransmitter’?
Box 5A, Neuroscience, chapter 5
Steroid Hormones can Serve as Neuromodulators
Examples:
• Estrogen
• Progesterone
• Testosterone
• Cortisol
Tissue origin (main)
• ovaries
• ovaries
• testes
• adrenal cortex
Some associated behaviors:
• mating & reproduction
• aggression
• maternal behaviors & lactation
• fear / anxiety response
Estrogen receptors in brain
Corticosterone uptake in hippocampus
Mechanisms of Steroid Action on Neurons
lipid