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L27 Cell Signalling (Intra(C) messengers (Functions of intra(c) mess
the…
L27 Cell Signalling
Intra(C) messengers
1st Mess
- extra(C) molecs tht bind to Rs
- the lgd binding to the Rs stimulates the 2nd mess
2nd Mess
- intra(c) molecs tht relay the signal thru the (C)
- recieve the signal from the extra(C) mess via the Rs
- can be small molecs (eg GTp, cGMP, cAMP, Ca2+, IP3 etc)
- can be h20-sol & ∴ present in the cytoplasm or can be lipid sol & diffuse along the plane of the memb (eg. diacylglycerol)
- can be prots eg. SHC, Grb2
- role of 2nd mess: pass the signal the the (C) ultimately binding to & changing the effector prot
Effector prots
- responsible for modifying the (C) behaviour
- gves the final response f the (c) to the OG sig
- stimulated by 2nd mess
Functions of intra(c) mess
- the relay of events tht occur inside the (c) have the following functions:
- Transform the signal into a molecular form tht can be passed along the pathway & ultimately stimulate a response
- The signal must be relayed from the primary receiving site to the final response production site.
- Smtms the sig is amplified along the signalling cascade. This strengthens the signal (a single extra(c) molec can have a much more pronounced effect on the (c))
- The signal may have to be distributed so tht it influences more than one process in parallel
- The relay may be modulated by other factors along the pathway- these factors may come from other 1o signalling molecs
(c)-surface Rs relay signals via intra(c) signalling molecs
- signalling by phosphorylation
~ kinases phosphorylate targets
~ kinase to activate
~ phosphatatse to inact
- signalling by GTP binding
~ exchange GDP to GTP to activate
~ GTP hydrolysis to inact
-
GPCRs
- form largest fam of (C)surface rs, >700 GPCRs in humans
- Stimulation of GPCRs activates Gprot subunitss
- Mediate responses to enormous diversity of extra(C) signal molecs
- some bacterial toxins cause disease by altering the activity of Gprots
- Many Gprots activate memb-bound ezms tht prod small (2nd) mess molecs
St
- all GPCRs have sim st
- polypeptide chain traverses memb as 7-alpha helices
- Cytoplasmic portion bind to a G prot inside the (C)
- Rs tht recognise sml molecs, binds deep in memb
- E.g. Adrenaline
- Rs tht bind prots have lge extra(c) domain
St of inactive G prot
- G prot = 3 subunit (𝜶,𝜷,𝜸)
- Both 𝜷 & 𝜸 subunit have lipid tails tht help attach to memb
- unstimulated state, 𝜶 subunit had GDP bound = inactive [relay no sigs to (c)
- GPCR active = 𝜶 sbunit ⇊ affinity to GDP, exchange for GTP
- activated GPCR activates G prots- 𝜶 subunit exchanges GDP to GTP
- Unstimulated state, both Rs & G prot inactive
- Binding extra(c) signal molec to Rs ∆s conformation. Alters conformation of G prot
- 𝜶 subunit exchange GDP to GTP
- Additional conformation ∆, 𝜶 & 𝜷𝜸 complex dissociate
- Interact w/ target prots
- G prot can interact w/ ion channels
- G prot directly couples Rs activation to opening of K+ channels in memb of heart pacemaker (c)s
- Acetylcholine to GPCR in heart (C)s
- 2 most freq targets for G prot are [1] adenyl cyclase, which prods sml intra(c) signalling molecs -> cAMP
- [2] Phospholipase C: generates inositol triphosphate & diacylglycerol
~ imositol triphosphate in turn promotes accumulation of Ca2+, [another sig mlec]
-
Some G prots signal via phospholipids
- some (c) responses in which GPCRs activate PLC𝜷
- Target tissue
~ liver →vasopressin → glycogen breakdown
~ pancreas → acetylcholine → amylase secretion
~ sm muscle → acetylcholine → muscle contraction
~ bld platelets → thrombin → platelet aggregation
Process
p the active GPCR stimulates memb bound phospholipase C-𝜷 via G prot
- two 2nd mess produced:
~ IP3 & DAG
- IP3= diffuses thru cytosol, released CA2+ from ER by binding & opening IP3 gated channels. Ca 2+ exits into cytosol
- DAG stays in memb, 2gth Ca2+ helps to activate prot kinase C
~ PKC phosphorylates its own set of intra(c) prots, propagating signal
Learning Outcomes
- Describe the 3 maj classes of (c) surface Rs
- define 1st, 2nd & effector molecs as signalling messengers
- describe function of intra(c) messengers
- describe st of a G-prot coupled Rs (GPCR)
- describe st of G-prot
- describe process of G-prot activation & inactivation
- describe the activation of GPCRs, including 2nd mess produced (using examples provided)