lecture 05 redone ppCNS

autocrine signalling

from a cell to its own receptors

paracrine signalling

from a cell to nearby targets

endocrine signalling

from a cell, goes to distant target cells further away (e.g., hormones secreted → bloodstream, or cytokines released @ site of inj)

primary vs secondary messengers

primary: carry signals b/w cells (NTs, hormones)

secondary: carry signals *within* cells AFTER primary messenger signalling

what are important processes secondary messengers carry out?

* nociception
* proliferation
* neurite growth
* gene expression

how can agonists produce different cellular responses (3)?

1. acting on different surface receptors
2. different actions on SAME receptor/2nd messenger
3. activating receptors that couple to multiple 2nd messenger pathways

how does the secondary messenger signal gain specificity?

this relates to the **selectivity of response**

utilises **spatial and temporal localisation**

describe spatial localisation

this refers to the **specific location of receptors within the body.** diff types of receptors are found in diff tissues and organs, and even __within the same tissue or organ__ diff types of receptors can be located in varying areas.

describe temporal localisation

refers to the **timing of receptor activation.** Receptors can be activated by a signal for a certain amount of time before they become desensitized and stop responding to the signal. The duration of receptor activation depends on a number of factors, such as the concentration of the signal and the rate at which it is being produced.

activation of 1 receptor by 1 extracellular transmitter can do what produce what ?

produce synth of multiple secondary messengers and alters activity of multiple targets (e.g., Adenylate Cyclase → cAMP)

why don’t cells always have all their signalling pathways switched on?

this related to **spatio-temporal localisation**

how does spatio-temporal localisation relate to stopping of secondary messenger activity?

stopping the activity of 2nd messengers quickly prevents unwanted signalling, and rapid on/off signals are more energetically efficient in temporal resolution.

3 major receptor classes with 2nd messengers

1. GPCRs
2. LGICs
3. TRK-linked receptors

what secondary messengers are GPCRs (and their assoc. G proteins) involved in?

1. Gs = ***ACTIVATES*** adenylate cyclase, increases \[cAMP\]
2. Go = ***INHIBITS*** adenylate cyclase, decreases \[cAMP\]
3. Gq = ***ACTIVATES*** Phospholipase C, increases \[IP3\] & \[DAG\]

what secondary messengers are LGICs involved in?

* Ca2+
* Na+
* Cl-
* K+

allow these ions to passively flow down their gradient, leading to shift in electrical charge and triggered cellular response

what 2 main types of enzyme-coupled receptors involve secondary messengers?

1. TRKs
* most common
* cannot phsoporylate their own Tyr-side chains, so when ligand binds, 2 receptor channels come together (like sandwich) + dimerise to cross-phosphorylate @ multiple Try residues to trigger conformational change
* conformation change makes high affinity binding sites for secondary messengers (which can also be phosphorylated to trigger signalling pathway)
2. Ser/Thr kinases
* have ser/thr kinase domain on intracellular end
* T1 & T2 receptors; ligand binding brings both together, T2 phosphorylates & activates T1, which then receipts & phosphorylates several target proteins to relay signal

how do GPCR-G protein subunits activity lead to turning on/off the G protein (GDP/GTP)?

activation (GDP)


1. when inactive, G proteins bind to GDP
2. when alpha subunit is bound to GDP, alpha, ß, and gamma subunits remain together for ligand to bind. this causes GPCR to change shape, allowing G-protein to release GDP & bind GTP instead which **activates protein**

inhibition (GTP)


1. when alpha subunit is bound to GTP, it separates ß and gamma subunits, allowing them to act freely.
2. alpha subunit must turn GTP → GDP to act on other proteins, so 3 subunits come back together and G protein is turned off.

describe the roles of Gs and Gi in adenylate cyclase

**Gs**: activates AC

* AC takes ATP & removes 2 P grps → cAMP
* cAMP moves thru cytoplasm & binds to PKA (which has 2 subunits; catalytic & regulatory).
* cAMP binds reg subunit, allow catalytic to dissoc. and phosphorylate target proteins leading **cellular response**

**Gi**: inhibits AC

* causes negative feedback on Gs
* important to help inactivate cells

T/F: the effects of cAMP are mediated by pKA

true; upon binding of cAMP, causes conformational change to release catalytic subunit so they move away to target Ser/Thr residues to phosphorylate them and trigger cellular response