Calcium

Calcium- and Phospholipid-Based Signal Transduction

Ca⁺⁺ is used as an Intracellular Signal – so cells must keep resting cytosolic Ca⁺⁺ levels low

Ca⁺⁺-ATPase in plasma membrane
Na⁺-Ca⁺⁺ exchanger in plasma membrane – only functions at elevated cytosolic Ca⁺⁺ levels
Ca⁺⁺-ATPase in ER
Ca⁺⁺-pump in inner mitochondrial membrane – only functions at dangerously high levels

Ca⁺⁺ Functions as a Ubiquitous Intracellular Messenger

muscle contraction, secretion, cell proliferation

Phospholipase C and the IP₃ Signalling Pathway

Some G-Protein-linked Receptors Activate the IP₃ Signaling Pathway by Activating Phospholipase C

signaling molec binds to G-protein-linked receptor

activated receptor stimulates Gq to activate phospholipase C (found in lipid bilayer)

phospholipase C cleaves PIP₂ Þ IP₃ + DAG

IP₃ binds to IP₃-gated Ca⁺⁺-release channels in ER memb Þ Ca⁺⁺ efflux into cytosol (+ feedback)

Ca⁺⁺ causes Protein Kinase C to migrate from cytosol to plasma memb

DAG, Ca⁺⁺, and phosphatidylserine together activate Protein Kinase C (ser/thr protein kinase)

DAG can be further cleaved Þ arachidonic acid

Protein Kinase C (also called C-kinase or PKC) phosphorylates ser/thr residues on target proteins, which increases the transcription of specific genes

this activates a protein kinase cascade that leads to the phosphorylation and activation of a DNA-bound gene regulatory protein
activation of protein kinase C also leads to the phosphorylation of an inhibitor protein, thereby releasing a cytoplasmic gene regulatory protein so that it can migrate into the nucleus and stimulate the transcription of specific genes

Calmodulin – an ubiquitous intracellular Ca⁺⁺ receptor

has 4 Ca⁺⁺ binding sites (usually 2 are full at all times)

undergoes conformational change when it binds Ca⁺⁺ Þ binds to its target protein (various enzymes and memb transport proteins) and undergoes a further conformational change

activates the plasma memb Ca⁺⁺-ATPase

activates Ca⁺⁺/calmodulin-dependent protein kinases (CaM-kinases)

Interaction of Ca⁺⁺ Pathways with Other Signalling Pathways

Cyclic AMP pathways

signaling molec binds to G-protein-linked receptor

activated receptor stimulates Gs to activate adenyl cyclase (found in lipid bilayer)

adenyl cyclase cleaves ATP Þ cyclic AMP which activates Protein Kinase A (also called A-kinase or PKA)

protein kinase A phosphorylates the IP₃ receptor in the ER which can inhibit or induce Ca⁺⁺ release

Receptor tyrosine kinases

Phosphorylated Tyrosine Residues Are Recognized by Proteins with SH2 Domains

signaling molec binds to receptor tyrosine kinase (RTK) Þ dimerization of RTK subunits causing activation of the intracellular kinase domain

the intracellular parts of the receptor become autophosphorylated on multiple tyr residues

substrate proteins with an SH2 domain (such as Phospholipase C) bind to the phosphotyrosines and become activated

Phospholipase C cleaves PIP₂ Þ IP₃ and DAG Þ see above for effects