The Inositol Triphosphate / Diacylglycerol / Calcium Second Messenger System

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The cell membrane is made up of phospholipids, molecules with a polar (water-loving, hydrophilic) head group and two non-polar (water-hating, hydrophobic) tails. This is shown in almost every representation of the neuronal cell membrane in this book.

One of these molecules, phosphatidylinositol (PI), plays a key role in intracellular chemical signaling. While the lipid tails vary (these are shown in this skeletal chemical diagram by the zigzag lines), the bridging three-carbon glycerol molecule is invariant.

(The glycerol molecule is shown here in the middle of this diagram with carbons numbered 1, 2, and 3.)

The six-sided figure at the bottom that looks vaguely like a chair is the sugar inositol. Its six carbons are numbered 1-prime (1′), 2-prime (2′), and so forth. There is a phosphate group (PO₄) attached to both the glycerol and inositol in a bond called a phosphodiester linkage. That bridging phosphate is connected to the 1′ carbon. The 4′ and 5′ carbons of inositol are also bound to phosphate groups in the molecule shown here, phosphatidylinositol 4′,5′-bisphosphate (PIP₂). Based on the concentration of PIP₂ in red blood cells, scientists estimate that PIP₂ makes up about 1% of the phospholipid molecules in the neuronal membrane.

PIP₂ has an almost uncountable number of roles in the neuron. These many roles can be sorted into two groups, however.

First, PIP₂ interacts directly with ion channels embedded in the cell membrane. An example of this is the interaction between PIP₂ and the G protein-gated inwardly rectifying K⁺ (GIRK) channels mentioned previously. PIP₂ can direct components of the neuronal membrane to various locations in the cell. Probably the most important direct action of PIP₂, however, is the interaction with the neuronal cytoskeleton. PIP₂ stabilizes actin filaments and is essential for the growth of neurons both in developing and in mature neurons.

The second group of functions dependent on PIP₂ use this molecule as a substrate for the creation of other intracellular signaling molecules. The enzyme phospholipase C cleaves the PIP₂ molecule between the #3 carbon of glycerol and the phosphate group, creating two new signaling molecules: diacylglycerol (DAG), which stays anchored in the neuronal membrane, and inositol 1, 4, 5-trisphosphate (IP₃), which moves around in the cytoplasm as a second messenger molecule.

DAG activates a number of other systems in the neuron:

• protein kinase C (PKC), which in turn triggers intracellular signals and gene expression leading to proliferation, survival, apoptosis, and motility;
• protein kinase D (PKD), which controls proliferation, survival, gene expression, vesicular trafficking, and neuronal development;
• DAG kinases (DGKs), involved in proliferation and the cytoskeleton;
• chimaerin, which is also involved in neuronal development;
• Munc13, one of the key proteins in vesicle fusion and exocytosis.

The second signaling molecule created from the enzymatic cleavage of PIP₂ is the sugar-phosphate part, inositol 1,4,5-triphosphate (IP₃). The main role of IP₃ is as a ligand for the ryanodine receptor, which releases Ca²⁺ from intracellular stores (generally, the smooth endoplasmic reticulum in neurons and the sarcoplasmic reticulum in muscle cells).

When these systems are triggered by a G protein-coupled receptor, the G protein which transduces the signal is called a G_q.

(Remember that we have already seen G_s proteins which stimulate cAMP production, and G_i proteins which inhibit cAMP production. Unlike the letters “s” and “i”, the letter “q” in G_q proteins carries no meaning at all and is merely a convenient letter of the alphabet.)

An example of a receptor whose signal transduction is dependent on a G_q protein is the alpha-1 (α₁) adrenergic receptor. (Even though the naturally occurring ligand for this receptor is either called norepinephrine or noradrenaline, the receptor is called adrenergic.) The α_q subunit carries a lipid anchor which holds it in the plane of the membrane. It slides in a plane just inside the inner leaflet of the neuronal membrane where it collides with, and activates, phospholipase C. PLC splits PIP₂ into DAG, which activates protein kinase C, and IP₃, which releases Ca²⁺ from intracellular stores.