Membrane Transport Processes and Signalling

Membrane Receptors

If the messengers are faulty, then you can get unregulated division - or cancer.

All receptors have to:

• Recognise a specific signal
• Initiate a cellular response

Some faulty receptors are called constitutively active, where a receptor signals continously.

Examples of Ligand Gated Ion Channels

• nicotinic acetylcholine receptor (nACHR) which controls Na⁺ flow.
• GABA (gamma-aminobutyric acid) receptor (controls Cl^- flow)
• Glycine receptor (again, controls Cl^- flow).

all have the same basic subunits (see above).

Examples of G-Protein Coupled Receptors

• Muscarinic Acetylcholine Receptors (mAChR)
• Adrenergic Receptors

Effects mediated by G-Proteins - G=Guanine Nucleotide Binding Regulatory Protein.

G-Proteins

heterotrimeric GTPases

The trimer consists of three different subunits:

1. Alpha

These are of molecular mass 29-52kDa, and have GTPase activity. There are many varietys of alpha subunits known.
2. Beta

These are of mass 35-37kDa. There are 5 or 6 known types of beta subunit
3. Gamma

Gamma subunits weigh between 7 and 10 kDa; there are 3 known types of gamma subunit.

Many different G-Proteins have been identified. The main difference is in the alpha subunit. Despite the differences in structure all the G-Proteins function in the same way.

Adenylate Cyclases (A.C.) also called Adneylyl Cyclases

This is a membrane bound enzyme (although iso-enzymes exist).

The switch off mechanism is Phosphodiesterase. You can increase the cAMP concentration by either activating Adenylate Cyclase or inihibiting cAMP-PDE - Coffee performs this latter action, which is one of the reasons it gives you a ‘buzz’

When the alpha_i subunit is involved it stimulates the receptor but inhibits the adenylaste cyclase, the alpha_r stimulates both the receptor & the adenylate cyclase.

Protein Kinase A (PKA)

PKA is activated by cyclic AMP, it phosphorylates specific Serine and Threonine residues:

Arginine - Anything - Serine/Threonine

It consists of 4 subunits, 2 regulatory and 2 catalytic:

Vision

Origin of Impulses in The Optic Nerve from the Retina of the Eye

1. Light activated rhodopsin promotes dissociation of residues (in G-Protein).
2. TD_(alpha) activates a specific cGMP phosphodiesterase.
3. [cGMP] decreases, leading to closure of an ion-channel.
4. This causes a decrease in Na⁺ influx, giving a hyper-polarised cell - This gives a nerve impulse.

Note that PDE activates signal not terminates signal as with cAMP

Phosphoinocitidase C (PIC)

a phospholipase C (PLC) - activation of PIC requires two messengers:

• DAG (DiAcylGlycerol)
• Inositol (1,4,5)trisphosphate (or Ins(1,4,5)P₃)

PKC (requires Ca²⁺, PS) + DAG ---> Increase in PKC Activity --->
Inorganic P_n of substrates in cell ---> Effects

The concentration of Calcium inside cells is generally around 1mM, but most is bound to protein, etc.

Calmodulin (CaM)

Calmodulin is a 17kDa ‘ubiquitous’ protein, with 4 calcium (²⁺ binding sites.

For example, and increase in AC, PDE and Ca²⁺ ATPase. - It serves as a Ca²⁺ activated switch

Vasopressin (Angiotensin II) -> Increase in PIC activity -> Increase in [Ca²⁺]

and, Calcium + Calmodulin increases Glycogen Phosphorylase Kinase activitu leading yo Glycogenisis.

What reasons are there for such a complex enzyme cascade? It gives amplification; at each and every step 1 will activate many, giving extraordinary amplification.

Hormonal Regulation of Glycogen Metabolism