306

22

Biological Signalling

or pumps, or by letting inorganic ions move down a diffusion gradient or actively

moving them in and out of the cell. Channels can be opened or closed by an external

ligand binding to part of the channel, resulting in a conformational change. The ions

act as mediators within the cell.

22.1

The Complexity of Signal Transduction

Analogously to polygeny, some receptors may only act on, or to produce, an effector

if they receive multiple and diverse molecular stimulants; conversely, analogously

to pleiotropy, some activated receptors may initiate multiple and diverse signalling

pathways. Biochemical signalling is suffused with combinatorial complexity. ³ The

cytoplasm is a crowded milieu in which free diffusion of molecules is impossible.

Much use is made of spatial organization. ⁴ The cytoskeleton may be employed as a

system of tracks along which signalling molecules may travel. ⁵

22.2

Anatomy of Signal Transduction

As an example of a well-established signalling pathway, consider the stimulation of

glycogenolysis in the liver cell to yield blood glucose. Some kind of stimulus causes

the adrenaline medulla to release the hormone epinephrine into the blood, where it

typically attains a concentration of about 1 nM. Receptors on the outer surface of

the liver cell membrane capture the epinephrine and activate the enzyme adenylate

cyclase (see Sect. 22.4 for the general mechanism), which decomposes ATP in the

cytoplasm to cAMP and inorganic phosphate. The cAMP activates protein kinase,

which phosphorylates dephospho-phosphorylase kinase, thereby activating it (using

phosphate from ATP, with ADP as a by-product). The phospho-phosphorylase kinase

then phosphorylates phosphorylase b, which is inactive, converting it to phosphory-

lase a, which is active, again using ATP. Phosphorylase a phosphorylates glycogen

using inorganic phosphate to produce glucose 1-phosphate, which is converted in

turn to glucose 6-phosphate, then glucose (releasing inorganic phosphate), which is

then released into the blood to reach a concentration of about 5 mM. The ratio of

concentrations of the molecular stimulant (epinephrine) and the ultimate result of the

stimulus, the metabolite glucose, is about5 times 10 Superscript 65 × 10⁶; hence this pathway is sometimes

referred to as an “amplification cascade”. ⁶ Unlike electronic amplification, in which

3 Hlavacek et al. (2006).

4 E.g., Fisher et al. (2000), Akhtar and Gasser (2007).

5 Forgacs (1995), Shafrir et al. (2000).

6 There is some arbitrariness in the deduction of amplification factors. For example, if the metabolite

coursing in human blood caused its host to operate a lever in a factory producing epinephrine, the

factor might be many, many orders of magnitude greater.