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Cell Signalling Biology Michael J. Berridge Module 2 Cell Signalling Pathways 2 51

Module 2: Figure InsP 3 /Ca 2 + signalling functions

Proliferation
Metabolism T cell Fertilization Exocytosis
Contraction Liver cells Mesangial cell b-Cell
Smooth muscle Smooth muscle L Cell
Mesangial cell Brown fat cell Mast cell,
Modulation of Macrophage
ventricular and Parathyroid gland
atrial cell contraction Piuitary cells
Astrocytes
Fluid secretion Renin-producing
Intestinal cell granular cells
Parietal cell
Pancreas 2+ Chemotaxis
Salivary gland InsP /Ca Neutrophils
3
Sweat gland Osteoclast
precursors (?)
Aldosterone
secretion
Glomerulosa cell Differentiation
Osteoclasts
Brown fat cells
Aggregation
Blood platelets Neuronal synaptic Ion channel
Sensory systems plasticity opening
Taste cells Purkinje neurons Astrocytes
Hippocampal neurons T Cells

InsP 3 /Ca 2 + signalling functions.
The mobilization of Ca 2 + by inositol 1,4,5-trisphosphate (InsP 3 ) functions in the control of many different cellular processes in a wide range of cell
types.

to form monoacylglycerol (Module 2: Figure InsP 3 /DAG phorylated by InsP 3 3-kinase to form Ins1,3,4,5P 4 (Step 4).
recycling). This hydrolysis of DAG, which is a Ca 2 + - These two products then enter a complex metabolic path-
sensitive process, may represent the primary mechanism way that plays an important role in recycling the inositol
for removing the DAG that is produced following the headgroup. Cells have access to three separate sources of
hydrolysis of inositol lipids. inositol: recycling the second messenger InsP 3 , de novo
The 2-arachidonylglycerol (2-AG) formed by DAG synthesis from glucose 6-phosphate or uptake of diet-
lipase is one of the endocannabinoids that has multiple ary inositol circulating in the plasma (Module 2: Figure
messenger functions. InsP 3 /DAG recycling). Drugs such as lithium and val-
proate may control manic-depressive illness by reducing
Inositol 1,4,5-trisphosphate (InsP 3 )and Ca 2 + signalling the supply of inositol by inhibiting the inositol mono-
The primary function of inositol 1,4,5-trisphosphate phosphatase and inositol synthase respectively. The sup-
(InsP 3 ) is to function as a second messenger to release ply of free inositol is one of the essential precursors for the
Ca 2 + from the internal stores. The 1,4,5-trisphosphate re- synthesis of PtdIns.
ceptors (InsP 3 Rs) located on the endoplasmic reticulum
respond to InsP 3 by releasing puffs of Ca 2 + (Module 3:
Synthesis of PtdIns
Figure InsP 3 R activation). These InsP 3 Rs are sensitive to
The two second messengers that are formed during phos-
both InsP 3 and Ca 2 + and can thus function as co-incident
phoinositide signalling can be recycled back to the pre-
detectors (Module 2: Figure Ca 2 + -induced Ca 2 + release). cursor lipid PtdIns4,5P 2 through a series of steps (Module
This InsP 3 /Ca 2 + signalling system controls many differ- 2: Figure InsP 3 /DAG recycling):
ent cellular processes in a large number of different cell
types (Module 2: Figure InsP 3 /Ca 2 + signalling functions).
1. Conversion of PtdIns into the precursor lipid
PtdIns4,5P 2 .
Inositol 1,4,5-trisphosphate (InsP 3 ) metabolism 2. The agonist-dependent activation of phospholipase C
The inositol 1,4,5-trisphosphate (InsP 3 ) that is formed dur- (PLC), which hydrolyses PtdIns4,5P 2 to generate the
ing signalling enters the pathways of inositol phosphate second messengers inositol 1,4,5-trisphosphate (InsP 3 )
metabolism from which it emerges as free inositol. It is and diacylglycerol (DAG).
dephosphorylated by Type I inositol polyphosphate 5- 3. The InsP 3 is recycled back to free inositol by a com-
phosphatase (Steps 1 in Module 2: Figure inositol phos- plex metabolic pathway illustrated in Module 2: Figure
phate metabolism) to form Ins1,4P 2 or it can be phos- inositol phosphate metabolism.

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