Q36: Define the term “Second Messenger Systems?

Second Messenger Systems

Second messenger systems are complexes of regulatory (eg, G-proteins) and catalytic (eg, adenylate cyclase, phospholipase C) proteins, which are activated by NTs (first messengers) to form specific chemicals or second messengers (eg, cAMP, inositol triphosphate or IP3, diacylglycerol or DAG).

Adenylate cyclase-cAMP is the best known second messenger system.  Here, the first messenger (NT, hormone) binds to the receptor activating a stimulatory G-protein  (Gs) by displacing guanosine diphosphate (GDP) with guanosine triphosphate (GTP). G-proteins consist of alpha, beta, and gamma subunits; the alpha unit binds the guanine nucleotide and provides specificity for receptors.  The activated protein amplifies the signal of the first messenger and activates adenylate cyclase.  This enzyme converts adenosine triphosphate (ATP) to cAMP, which activates specific phosphorylating enzymes or protein kinases to produce the physiologic response.  The action of cAMP is terminated by the enzyme phosphodiesterase.  In addition to the stimulatory G-protein, inhibitory G-proteins (Gi) exist.  By activation of a different receptor and this Gi, adenylate cyclase is inhibited.  In each category, different G-proteins have been identified (Gs1, Gs2, Gs3 and Gi1, Gi2, Gi3).

Phosphoinositide system – generates 2 second messengers, IP-3 and DAG.  Upon receptor stimulation and G-protein activation, phospholipase C is stimulated, which hydrolases membrane phosphatidyl inositol 4,5-biphosphate into IP-3 and DAG.  IP-3 releases calcium from intracellular stores, and DAG activates protein kinase C. Effects on ion channels or phosphorylation of specific proteins causes the physiologic effects.

Types of secondary messenger molecules

There are three basic types of secondary messenger molecules:

• Hydrophobic molecules: water-insoluble molecules, like diacylglycerol, andphosphatidylinositols, which are membrane-associated and diffuse from theplasma membrane into the intermembrane space where they can reach and regulate membrane-associated effector proteins
• Hydrophilic molecules: water-soluble molecules, like cAMP, cGMP, IP₃, andCa²⁺, that are located within the cytosol
• Gases: nitric oxide (NO) and carbon monoxide (CO), which can diffuse both through cytosol and across cellular membranes.

These intracellular messengers have some properties in common:

• They can be synthesized/released and broken down again in specific reactions by enzymes or ion channels.
• Some (like Ca²⁺) can be stored in special organelles and quickly released when needed.
• Their production/release and destruction can be localized, enabling the cell to limit space and time of signal activity.

Common mechanisms of secondary messenger systems

There are several different secondary messenger systems (cAMP system,phosphoinositol system, and arachidonic acid system), but they all are quite similar in overall mechanism, though the substances involved in those mechanisms and effects are different.

In all of these cases a neurotransmitter binds to a membrane-spanning receptor proteinmolecule. The binding of the neurotransmitter to the receptor changes the receptor and causes it to expose a binding site for a G-protein. The G-protein (named for the GDPand GTP molecules that binds to it) is bound to the inner membrane of the cell and consists of three subunits: alpha, beta and gamma. The G-protein is known as the “transducer.”

When the G-protein binds to the receptor, it becomes able to exchange a GDP (guanosine diphosphate) molecule on its alpha subunit for a GTP (guanosine triphosphate) molecule. Once this exchange takes place, the alpha subunit of the G-protein transducer breaks free from the beta and gamma subunits, all parts remaining membrane-bound. The alpha subunit, now free to move along the inner membrane, eventually contacts another membrane-bound protein – the “primary effector.”

The primary effector then has an action, which creates a signal that can diffuse within the cell. This signal is called the “secondary messenger.” (The neurotransmitter is the first messenger.) The secondary messenger may then activate a “secondary effector” whose effects depend on the particular secondary messenger system.

Calcium ions are responsible for many important physiological functions, such as in muscle contraction. It is normally bound to intracellular components even though a secondary messenger is a plasma membrane receptor. Calcium regulates the protein calmodulin, and, when bound to calmodulin, it produces an alpha helical structure. This is also important in muscle contraction. The enzyme phospholipase C producesdiacylglycerol and inositol triphosphate, which increases calcium ion permeability into the membrane. Active G-protein open up calcium channels to let calcium ions enter the plasma membrane. The other product of phospholipase C, diacylglycerol, activatesprotein kinase C, which assists in the activation of cAMP(another second messenger).

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