The Inositol Triphosphate / Diacylglycerol / Calcium Second Messenger System

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.

Vivamus malesuada, eros eget rutrum ullamcorper, purus nibh elementum elit, vel placerat orci dolor id neque. Maecenas facilisis gravida felis id accumsan. Quisque ut luctus eros, sed faucibus purus. Etiam in magna pulvinar, dignissim sem at, dictum nulla. Proin congue nisi cursus turpis faucibus, a maximus velit dapibus. In mollis enim non dui malesuada viverra. Aenean cursus enim vel congue dictum. Proin sit amet mi quis nulla venenatis rhoncus. Nunc vitae sem eu erat vestibulum ultrices eu ac ex. Pellentesque sit amet ante nisi. Curabitur rhoncus ipsum vel maximus molestie. Nam sit amet mattis quam, et mollis felis. Nulla bibendum fermentum augue sed ornare. Suspendisse fermentum tellus sed turpis gravida vulputate. Pellentesque interdum, est at dictum interdum, diam ipsum rhoncus nisi, quis porta mauris libero eget eros.

In hac habitasse platea dictumst. Donec porta eget tortor in hendrerit. Nulla justo urna, pharetra eget malesuada ut, placerat vitae lorem. Integer mollis metus nibh, nec condimentum libero laoreet et. Mauris fermentum at magna vitae ullamcorper. Aliquam at feugiat tellus. Pellentesque pharetra malesuada elit. Sed pretium convallis purus vel consequat. Quisque a tellus libero. Praesent vitae diam eros.

Nullam vitae eros velit. Sed pharetra in erat nec venenatis. Maecenas maximus nisi justo, sit amet ultricies leo molestie et. Ut et eros sed eros pharetra mollis. Nulla facilisi. Pellentesque cursus consequat nisl, sed congue massa molestie in. Aenean quis tincidunt lacus. Vivamus at laoreet erat, tempus aliquam velit. Mauris vehicula mi sit amet lorem viverra, sit amet ornare nibh lobortis. Etiam eu felis vitae dolor pretium accumsan. Morbi ullamcorper ante ut arcu mattis iaculis.

Cras elementum feugiat purus at dignissim. Nunc ac ante porta neque molestie scelerisque a a erat. Nulla tempus vestibulum vulputate. Fusce imperdiet aliquet arcu. Nam consectetur molestie nisl, ut luctus ante sagittis vitae. Nullam efficitur nibh sit amet odio ultricies porttitor. Vivamus ac venenatis arcu. Pellentesque eu ante ac elit commodo mollis a vehicula libero. Sed eleifend diam dui, et eleifend eros posuere id. Donec volutpat turpis ipsum, quis porta diam interdum id. Ut felis nisl, blandit ut tristique sodales, blandit eu tortor. Maecenas quis tempor justo, nec hendrerit arcu. Aenean et sapien risus. Donec pulvinar, sapien id tristique tincidunt, ligula est mollis lacus, vitae fermentum metus ligula at purus.

Pellentesque pharetra eros in erat dictum, egestas vulputate ligula interdum. Quisque eu nulla vitae massa scelerisque luctus. Nunc non imperdiet sem, vitae tincidunt erat. Nullam luctus posuere nisl, non sagittis nibh. Sed ut purus blandit sem gravida posuere vitae id orci. Maecenas elementum, arcu a dapibus pretium, leo metus aliquet ante, in ornare magna massa a felis. Curabitur pharetra hendrerit nibh eu commodo. Proin posuere dolor vitae sem pretium, commodo congue lectus tempus. Donec non viverra erat, ut tristique justo. Proin vitae ultrices diam, nec aliquet diam. Aenean fringilla, orci nec suscipit porttitor, mi libero egestas est, eget gravida ex diam hendrerit velit. Nullam lacus dui, convallis venenatis eleifend eu, fermentum ac elit. Curabitur lectus arcu, ullamcorper non rutrum imperdiet, gravida at risus. Nam suscipit augue at orci congue, sit amet aliquet dolor efficitur.

Mauris vel neque mauris. Nunc accumsan sollicitudin velit, a commodo velit pharetra vitae. Morbi tincidunt purus in quam dignissim eleifend lobortis non orci. Etiam eros enim, consectetur quis dui vel, volutpat ultricies justo. Morbi maximus volutpat metus, eu venenatis dui pellentesque quis. Nunc vehicula nulla nec volutpat consectetur. Aliquam sed erat tellus. Mauris pulvinar risus a augue aliquet fringilla. Nunc pharetra laoreet commodo. Aliquam erat volutpat. Nunc posuere tortor pellentesque ante sodales, non sodales nunc suscipit.

Fusce semper a orci non imperdiet. Nulla luctus ante vel tellus hendrerit, tincidunt condimentum nulla tristique. Sed tincidunt ligula eget scelerisque aliquet. Nam vestibulum porttitor quam, at posuere mauris suscipit eget. Nulla luctus turpis nec feugiat condimentum. Suspendisse porttitor enim eget lectus cursus pellentesque. Cras cursus tortor id maximus aliquam. Aenean mauris neque, gravida et elementum vitae, egestas congue diam. In non enim nec mi pulvinar consectetur ut ultrices libero.

Donec sit amet ipsum mattis felis tincidunt consectetur. Morbi eu leo imperdiet, auctor tellus eget, tempor tortor. Donec tempus tellus sit amet purus eleifend tempor. Fusce et risus nisi. Curabitur rutrum nibh ut turpis convallis, quis imperdiet ex vestibulum. Pellentesque varius eros risus, id scelerisque eros porttitor sed. Nunc ullamcorper a turpis vel interdum. Duis tempus tempus lectus, id dignissim libero tempus at. Mauris velit mauris, luctus vitae nunc ac, elementum tincidunt dolor. Cras egestas pulvinar augue, a sagittis elit fringilla sit amet. Maecenas sit amet mi ex. Pellentesque scelerisque vitae arcu et laoreet. Fusce tincidunt elit at enim imperdiet, eget malesuada lacus iaculis. Fusce in volutpat libero.

In accumsan nunc ac mauris commodo condimentum. Morbi rhoncus ornare gravida. Donec eu sem imperdiet, sollicitudin metus quis, rhoncus libero. In placerat metus imperdiet leo egestas tempus. Nunc efficitur mauris nec magna condimentum commodo. Nam faucibus tortor dolor, a dignissim tortor tempus iaculis. Suspendisse tempor euismod accumsan.

Nulla tempus interdum arcu at tristique. Donec iaculis magna quis dictum egestas. Quisque quis bibendum libero. Nunc consectetur fringilla tortor, nec lacinia neque tempor in. Nullam luctus ultrices blandit. Fusce pellentesque velit urna. Mauris eu tristique mi. Nunc euismod finibus posuere. Nulla facilisi. Praesent at massa nec lectus euismod faucibus et blandit lectus. Praesent enim sapien, tempus sed odio ac, placerat feugiat lectus. Duis venenatis sed nunc vitae egestas. Ut interdum nunc non nunc aliquet condimentum. Pellentesque facilisis dignissim vehicula.

Ut in tortor ultrices, faucibus nulla eget, interdum nisl. Nam scelerisque vehicula metus et suscipit. Nullam magna ligula, porttitor id enim eu, imperdiet sollicitudin risus. Mauris interdum non mauris eget blandit. Ut varius, nunc vel pretium rutrum, eros ex dapibus sapien, in dignissim turpis nisi vel erat. Integer vulputate finibus metus. Vestibulum dictum mauris eget eros aliquam, eu laoreet magna consectetur. Suspendisse feugiat, turpis pulvinar euismod imperdiet, dui mi feugiat nisi, at pretium metus nunc at dui. Sed tincidunt felis magna, eu convallis risus rhoncus ac. Nam sed dapibus erat. Donec quam arcu, suscipit ut augue sit amet, venenatis tempor orci. Nam eu ligula rutrum, efficitur massa eget, faucibus ex. Sed sollicitudin ultrices sem vel mattis. Phasellus rutrum dignissim dui, ac rutrum elit luctus vitae. Maecenas hendrerit dui ut neque ullamcorper tincidunt. Nunc elementum purus sem.

Morbi efficitur id dolor non faucibus. Aliquam aliquet porttitor lacus non pulvinar. Etiam at porttitor leo, lobortis pretium magna. Mauris ullamcorper cursus auctor. In hac habitasse platea dictumst. Maecenas rutrum, justo malesuada gravida aliquam, tortor nisi scelerisque orci, sit amet pretium lacus turpis ac velit. Duis in nisi sed odio blandit hendrerit non id felis.

Praesent luctus ante congue, vestibulum tortor eget, mollis justo. Quisque ipsum nisl, finibus eget sagittis nec, lobortis eget tellus. Maecenas mattis ante mauris, ut dapibus dui blandit a. Duis fermentum scelerisque quam, eget mollis nisl elementum id. Vivamus eu ligula lacinia, volutpat ex eu, mollis sem. Pellentesque id leo dolor. Sed vitae leo sollicitudin, bibendum nulla ut, fringilla purus. Morbi interdum tempus nulla at eleifend. Aliquam in quam at sapien porttitor lacinia. Maecenas in dictum nibh, faucibus elementum neque.

Vivamus rutrum metus sit amet felis facilisis, id vestibulum lacus finibus. Nulla nisi nulla, ultrices a sapien sit amet, condimentum ultrices tellus. Ut euismod facilisis eros in malesuada. Vivamus ultrices hendrerit lectus, sit amet egestas massa sodales vitae. Aenean aliquet libero nec elit consectetur, et tincidunt ipsum pharetra. Mauris fringilla tortor velit, eu imperdiet urna eleifend ac. Nulla at orci nunc. Mauris turpis tellus, porttitor et dictum ac, condimentum a nunc. Suspendisse ligula sem, tempus sit amet aliquam ac, mattis at ante. Integer in mauris id felis efficitur pharetra eget non mauris. Curabitur sodales mattis libero non lacinia. Vestibulum ante ipsum primis in faucibus orci luctus et ultrices posuere cubilia curae;

Sed efficitur malesuada rutrum. Ut nec tempus nisl, et interdum erat. Aliquam congue vitae lorem dapibus tempor. Integer eget tincidunt odio. Curabitur tristique sit amet tellus nec commodo. Donec diam lorem, rutrum non enim et, congue auctor lectus. Nulla ipsum turpis, blandit in sapien in, euismod mollis nibh. Morbi egestas sapien ac eros rhoncus porta. Nulla facilisi. Maecenas sollicitudin venenatis neque vel fermentum. Quisque dignissim ultrices lectus non mattis. Aliquam cursus sapien tellus, ornare feugiat libero semper sit amet.