Membrane structure

[box type=”download”]  The bilayer structure embedded with transport proteins  The importance of G-protein coupled receptors in activation of cellular activity  Note: A detailed knowledge of the G-proteins (s, i, q) is NOT required [/box]

Membrane lipids (mostly phospholipids) comprise a hydrophilic (water-loving) head, with two short
hydrophobic (water-repelling) fatty acid tails.
In an aqueous medium they self-organize into a bilayer with the heads facing outwards and the tails inwards. They diffuse freely within each layer (lateral diffusion) so the membrane is fluid.
Lipid-soluble (hydrophobic) substances such as cholesterol incorporate into the membrane, whilst molecules with both hydrophobic and hydrophilic domains such as proteins can be tethered part in and part out of the membrane.
Spectrin binds to the inner layer and forms an attachment framework for the cytoskeleton.
Lipid-soluble molecules such as O2 and CO2, and small molecules such as water and urea readily pass through the lipid bilayer.
However, larger molecules such as glucose and polar (charged) molecules such as ions need transporter and ion channels.
Proteins and large particles can also be engulfed by membrane segments to form intracellular vesicles (endocytosis).
Most cells are covered by a thin gel-like layer called the glycocalyx, containing glycoproteins and carbohydrate chains extending from the membrane and secreted proteins. It protects the membrane and also plays a role in cell function and cell–cell interactions.

Many receptors are members of the G-protein coupled receptor (GPCR) super-family with seven membrane-spanning domains
A)When inactive (no ligand), GPCRs attach to heterotrimeric G-proteins (guanine nucleotide-binding) consisting of a GTPase-containing α-subunit (Gα), and β and γ subunits (as a dimer, Gβγ).
At this point Gα is bound to GDP (guanosine diphosphate).
B)On GPCR activation by a ligand (e.g. neurotransmitter, hormone) or light for rhodopsin receptor, Gα exchanges GDP for GTP (guanosine triphosphate).
C) Gα-GTP and Gβγ dissociate from the GPCR and each other, though remaining tethered to the membrane.
Receptor tyrosine kinases (RTKs) are high affinity receptors for polypeptide growth factors, cytokines and insulin.
Ligand binding causes receptor dimerization and trans-phosphorylation of tyrosine residues in their cytoplasmic tails, creating a binding site for SH2 (Src-homology 2) and PTB (phosphotyrosine binding) domain proteins.
These initiate diverse signalling pathways, many affecting gene transcription, and regulate cell growth, proliferation, differentiation, survival and responses to stress and inflammatory cytokines.
Some RTKs also activate PLCγ, which like PLCβ generates inositol-trisphosphate (IP3) and diacylglycerol (DAG).
Protein kinases recognize target proteins by specific amino acid sequences (motifs).
The same motif can occur in different proteins, so a protein kinase can potentially phosphorylate multiple targets (different responses in different cell types).
Conversely two protein kinases may phosphorylate a single protein, but at different motifs which affect its function in different ways.


Cell signalling

Transmembrane proteins such as integrins and cadherins provide structural and signalling links with other cells and the extracellular matrix.
Their cytosolic ends bind to components of the cytoskeleton, including protein kinases.
Membrane-spanning proteins like ion channels and receptors allow signals to be transferred across the membrane.
Binding of a molecule (ligand) to its receptor initiates intracellular activation of enzymes attached to the membrane inner surface that generate second messengers to promulgate the signal.
Second messengers can be substrates for other enzymes, activate protein kinases which phosphorylate proteins to alter their function, or trigger a rise in cytosolic Ca2+ (itself a key second messenger).
Ca2+ may act directly (e.g. on troponin), or via the Ca2+ binding protein calmodulin (CaM), which on binding 4 Ca2+ activates Ca2+-dependent protein kinases (e.g. myosin light chain kinase, MLCK).
Membrane-bound enzymes generating second messengers include phospholipases and adenylate cyclase. Phospholipase A2 (PLA2) cleaves membrane phospholipids to release arachidonic acid, which is converted by cyclooxygenase (COX) into the substrate for synthesis of eicosanoids (prostaglandins and leukotrienes).
Phospholipase C (PLC) cleaves PIP2 (phosphatidyl inositol bisphosphate) into inositol-trisphosphate (IP3) and diacylglycerol (DAG), which evoke Ca2+ mobilization and activation of protein kinase C (PKC).
Adenylate cyclase generates cyclic adenosine monophosphate (cAMP) which activates protein kinase A (PKA), and guanylate cyclase generates cGMP (cyclic guanosine monophosphate), activating protein kinase G (PKG).
Both cyclases also have soluble (cytosolic) isoforms.
cAMP and cGMP also have kinase-independent effects, including activation of cyclic nucleotide-gated ion channels.
To terminate signalling, cytosolic Ca2+ is pumped back into the endoplasmic reticulum by SERCA (sarco/endoplasmic reticulum Ca2+-ATPase) and out of the cell by PMCA (plasmamembrane Ca2+- ATPase) and NCX (Na+-Ca2+ exchanger), cAMP and cGMP are broken down by phosphodiesterases, and proteins are dephosphorylated by phosphatases (though this activates some kinases).

Lesson tags: cadherins, calmodulin, cell signaling, cyclooxygenase, DAG, diacylglycerol, G protein, glycocalyx, GPCR, inositol-trisphosphate, integrins, IP3, motifs, NCX, phosphatidyl inositol bisphosphate, phospholipase A2, phospholipase c, PIP2, PMCA, Receptor tyrosine kinase, rhodopsin, second messengers, SERCA, spectrin
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