ch 3: chemical signalling in the NS

the basis of neuronal communication (3)

• communication btw neurons occurs at synapses via chemical NTs that cross the synaptic cleft

• transmission is one-way: pre → postsynaptic cell

• NT contained in synaptic vesicles

types of synapses (6)

1. axodendritic: axon to dendrite

2. axosomatic: axon to cell body

3. axoaxonic: axon to axon

4. neuromuscular junction: axon to muscle

5. electrical: electric current flows along specialized proteins → mediated by ∆s in membrane potential

6. mixed: both chemical + electrical transmission → release of NT bc of ∆ in voltage

criteria that makes a NT (4)

1. must be in brain

2. manufactured in synapse

3. has to be present + then removed when not needed → has to bbe specific signal

4. has to signal through some mechanism

classes of NT (5)

1. amino acids + monoamines

2. acetylcholine (ACh)

3. ATP and adenosine 

4. neuropeptides, lipids, gases 

5. elements → ie. Zinc but not manufactured 

how is the synthesis of neuropeptides different from other NTs 

1. most NT synthesized in axon terminals 

2. NPs are synthesized from precursor proteins that are synthesized in the cell body + shipped to the axon terminals 

3. replenishment of NPs is slower than for small-molecule NTs 

neuromodulators (3)

• alter the action of standard NTs 

• diffuse away frim the site of release to influence more distant cells → volume transmission

• some transmitters may act in both ways

classical NT release triggered by ___

1. triggered by Ca2+ influx at membrane depolarization

2. Ca2+ mediates release of transmitter from vesicles by exocytosis

define exocytosis (3)

• the fusion of the vesicle membrane  the membrane of the axon terminal

• exposes the inside of the vesicle to the outside of the cell

• vesicle is opened + NT molecules are allowed to diffuse into the synaptic cleft 

what are active zones (3)

• specialized regions near the postsynaptic cell where NT occurs

• stain darkly on the electron micrograph 

• vesicle must be transported to an active zone for exocytosis to occur 

three models of vesicle recycling

1. clathrin-mediated endocytosis 

2. ultrafast endocytosis 

3. kiss-and-run

clathrin-mediated endocytosis (3)

• After full-collapse fusion, vesicle membrane diffuses away from the release site

• Clathrin + adaptor proteins coat the membrane; dynamin pinches it off → new vesicle

• Time scale: ~10–20 s; supports low–moderate activity
  🧠 Takeaway: Full collapse → clathrin retrieval away from the active zone.

ultrafast endocytosis  (3)

• Within ~50–100 ms of fusion, membrane is rapidly internalized near the active zone (no clathrin yet)

• Internalized membrane forms an endosome; clathrin is used later to bud new synaptic vesicles from the endosome

• Operates under typical activity; faster local retrieval than classical clathrin
  🧠 Takeaway: Grab fast first (no clathrin), then rebuild vesicles from an endosome with clathrin.

kiss-and-run (3)

• Vesicle makes a transient fusion pore, releases transmitter, then reseals without full collapse

• Local, rapid reuse; clathrin not required for retrieval

• Minimizes mixing of vesicle/plasma membranes; evidence mixed/controversial
  🧠 Takeaway: Brief pore, quick reseal—vesicle “kisses” the membrane and “runs.”

what sets lipid + gaseous NTs apart from classic NTs? (3)

• not stored in vesicles

• synthesized on demand by postsynaptic cell after receptor activation by a classical NT

• act as retrograde messengers on the presynaptic cell + also diffuse to other neurons 

Classical synaptic transmission — step map (draw it)

• AP arrives → presynaptic depolarization → voltage-gated Ca²⁺ channels open → Ca²⁺ influx

• SNARE-primed vesicle fuses (Ca²⁺ sensor = synaptotagmin) → NT released

• NT binds ionotropic (fast) or metabotropic (GPCR) receptors → EPSP/IPSP

• Termination: reuptake (transporters), enzymatic breakdown, or diffusion; membrane retrieved by endocytosis
  🧠 Takeaway: Ca²⁺ + SNAREs → fusion; transporters/enzymes → signal off.

Synaptic vesicle cycle — reload & recycle (draw it)

• Endocytosis → budding of new vesicle → filled by vesicular transporters

• Docking & priming at active zone (SNARE complex assembled)

• Ca²⁺ entry triggers synaptotagmin-mediated fusion → exocytosis

• Membrane recycled (clathrin pathways) → refill → repeat
  🧠 Takeaway: Dock–prime–Ca²⁺ trigger–fuse–recycle = the loop that keeps release going.

mechanisms that control the rate of NT release by nerve cells (3)

1. rate of cell firing → how quickly an AP invades the terminal 

   1. (more APs → more Ca²⁺ entries → ↑ release)

2. probability of NT release → synapses vary in the probability that vesicles will undergo exocytosis 

   1. at the terminal (synapse-specific; # of docked/primed vesicles, Ca²⁺ coupling)

3. presence of autoreceptors → (usually ↓ further release)

3 kinds of autoreceptors

1. terminal: inhibit further transmitter release

2. somatodendritic: slow the rate of cell firing 

3. heteroreceptors: receive transmitters at axoaxonic synapses; either enhance or reduce transmitter release 

Terminal autoreceptors — function & mechanism (3)

• Located on presynaptic terminal

• Activated by the neuron’s own transmitter

• Inhibit further release/synthesis (negative feedback; often via ↓ Ca²⁺ entry or ↑ K⁺)
  🧠 Takeaway: Terminal autoR = “we’ve released enough—slow down.”

Somatodendritic autoreceptors — how are they different? (2)

• Located on cell body/dendrites of the same neuron

• Activation reduces firing rate (hyperpolarization), which indirectly lowers release at terminals
  🧠 Takeaway: Somato-dendritic autoR = turn down the pacemaker.

Heteroreceptors (axoaxonic control) — what do they do? (3)

• Presynaptic receptors activated by another neuron’s transmitter (not its own)

• Found at axoaxonic synapses

• Can decrease release (e.g., presynaptic inhibition via Gi GPCRs) or increase release (facilitation)
  🧠 Takeaway: Neighboring axons can dial your release down or up.

mechanisms of NT inactivation (3)

1. enzymatic breakdown w/in or near the synaptic cleft 

2. reuptake: removal from synaptic cleft by transporter proteins on the axon terminal membrane 

3. uptake by postsynaptic cell or glial cells 

Neurotransmitters outside the CNS — what to know (3)

• Many of the same transmitters exist inside & outside CNS

• Some are made by gut bacteria; drugs can alter the microbiome

• 🧠 Takeaway: Don’t think “brain-only”—transmitters act system-wide.

The gut–brain axis (bidirectional) (3)

• Two-way signaling between gut (incl. microbiome) and brain

• Pathways: vagus nerve + systemic routes (immune, endocrine, metabolites)

• 🧠 Takeaway: Gut activity can change brain function and vice versa.

Neurotransmitter receptors (4)

• Proteins on plasma membranes (neurons, muscle, secretory cells)

• Ligand binding → conformational change → response in the target cell

• Responses can be excitatory or inhibitory

• 🧠 Takeaway: Receptors translate chemical binding into cellular action.

Receptor subtypes (same NT, different outcomes) (5)

• A single NT has multiple receptor subtypes with distinct signaling

• Different subtypes ⇒ different effects & drug selectivity

  • ionotropic 

  • metabotropic

• 🧠 Takeaway: Which subtype is hit matters as much as which transmitter.

structure + function of ionotropic receptors (4)

• consists of multiple subunits that form a selective ion channel for specific ions (K+, Na+, Ca2+, Cl-)

• resting state = ion channel closed

• NT binding opens the channel → closes when NT dissociates 

• act rapidly + can undergo desensitization

structure + function of metabotropic receptors (4)

• consist of a single subunit that works by activating G proteins when NT binds

• G proteins open ion channels or stimulate/inhibit membrane effector enzymes

• acts slower but response lasts longer

• have additional binding sites → allosteric sites 

effector enzymes are involved in

synthesis or breakdown of 2nd messengers

allosteric modulators (2)

• bind to allosteric sites + modify (positively or negatively) the effects of an agonist 

• have potential for treating psychiatric + neurological disorders 

mechanisms of action of 2nd messengers

• activate protein kinases that phosphorylate another protein molecule

• the added phosphate groups alter functioning of the protein 

• includes cAMP, gAMP, Ca2+, PIP2 

phosphodiesterases (PDEs) + clinical uses (2)

1. inactivate 2nd messengers like cAMP + gAMP

2. inhibitors of specific PDEs may be useful in treating various CNS disorders 

phosphoinositide second-messenger system (5)

• breaks down a phospholipid in the cell membrane to form two 2nd messengers:

  • diacylglycerol (DAG)

  • inositol triphosphate (IP3)

• they cause ↑sed Ca2+ that activates protein kinase C (PKC)

• Ca2+ also activates calcium/calmodulin kinase II (CaMKII)

neurotrophic factors (4)

• action mediated by tyrosine kinase receptors

• stimulate the survival + growth of neurons during early development

• are involved in neuronal signalling

• these systems generally participate in regulation of long-term changes in gene expression + neuronal functioning

Ways drugs can modify synaptic transmission (overview) (5)

• NT Synthesis: ↑ as precursor or ↓ by enzyme inhibition

• Storage: block vesicle packaging (e.g., VMAT inhibitors)

• Release: stimulate or inhibit exocytosis

• Termination: block degradation (AChE/MAO) or block reuptake (SSRIs, cocaine)

• Receptors: agonize or antagonize postsynaptic receptors
  🧠 Takeaway: Think pre → during → post: make, store, release, stop, receive.

synaptic plasticity (4)

• functional ∆s → strength of existing synapses 

• structural ∆s → loss of synapses/growth of new ones (+dendritic spines)

  • ∆ in dendritic length, branching, spine density

• many abused drugs produce ∆s in neuron dendrites

adrenal glands secrete (2)

• adrenal medulla secretes epinephrine + norepinephrine (monoamines)

• adrenal cortex: secretes glucocorticoids → steroid hormones

gonads secrete (2)

• ovaries: estrogen + progesterone 

• testes: androgens → testosterone 

islets of Langerhans in the pancreas secrete (3):

• insulin 

• glucagon

• peptide hormones for the regulation of glucose 

thyroid gland secretes (3)

• thyroxine (T4)

• triiodothyronine (T3)

• regulate energy metabolism

melatonin is secreted by the ____ and controls ____

• pineal gland

• sleep + other rhythms

anterior pituitary secretes stimulation hormones (6)

1. TRH → TSH

2. CRH → ACTH

3. GnRH → FSH

4. GnRH → LH

5. GH

6. PRL

hypothalamus secretes ____ to trigger secretion of _____

• releasing hormones

• stimulating hormones by the anterior pituitary 

_______ are relased by neurons in the median eminence and are then carried by _____ to the ______

• hypothalamic releasing hormones

• blood vessels in pituitary stalk

• anterior pituitary

__1__ + __2__ are synthesized in the hypothalamus by neurons whose axons reach the posterior pituitary gland (+ their functions) → they are __3__ + influenced by __4__

1. vasopressin: regulates water retention in kidneys

2. oxytocin: stimulates uterine contractions during childbirth → triggers milk letdown from the breasts 

3. sexually dimorphic

4. gonadal steroids

VP + OT neurons from the _____ connect to many other brain regions which are part of or interact w the _______

1. paraventricular nucleus 

2. social behavioural neural network

oxytocin can influence a variety of _______, including: ____, altruism, ____, and social memory + it may have potential in what kinds of treatments?

1. social behaviours

2. empathy

3. trust

4. may have potential in ameliorating the social deficits in autism spectrum disorder patients

mechanism of hormone action 

• Most peptide hormones act through membrane metabotropic receptors.

• Insulin uses tyrosine kinase receptors.

• Steroid and thyroid hormones operate mostly through intracellular receptors in the cell nucleus; function as transcription factors.

why is the endocrine system important to pharmacologists? (4)

• Drugs can adversely alter endocrine function.

• Hormones may alter behavioural responses to drugs.

• Hormones sometimes have psychoactive properties.

• Because pituitary hormones are controlled by neurotransmitters in the brain, the endocrine system can tell us if a neurotransmitter system has been altered.