G Protein-Linked Receptors An organism must respond appropriately to its internal and external environments day after day in order to survive. The organism's cells respond to internal and external stimuli much like tiny computers that process numerous inputs and also produce numerous outputs in daily existence (Kennedy 2004). These stimuli are signals that come from the general environment or the cells of other or co-existing organisms, proximate or distant, and this exchange of stimuli and responses involves three sequential processes. These are signal that binds to the receptor protein, the binding that sends a message to the receiving cell's cytoplasm that amplifies it, and the receiving cell's change or response to the signal (Kennedy).

Cells must process the perceived information from the environment and form appropriate responses to it and not all cells can do this. In order to interpret signals, a cell should have the appropriate receptor protein (Kennedy 2004). Multi-cellular organisms possess the genetic information for all receptor proteins, but because there are differential gene expressions, different cells have different receptors. Signals, whether as chemical molecules or physical stimuli, and their interpretation constitute the order called life and these signals are used from the earliest stage of embryonic development to the death of the entire organism (Kennedy). They provide information to the cells of multi-cellular organism within a tissue, organ or the entire body, such as in wound healing, cell replacement or death, the moment-to-moment maintenance of sufficient and appropriate concentrations of nutrients and numerous other activities on the cellular to organic levels (Kennedy). This process requires a receptor, transduction and effects and cells possess specific receptor proteins for interacting to specific signals. Signal transduction is the change of a signal from one form to another and numerous transductions simultaneously occur through a pathway by means of blood circulation. A receptor changes form when binding and conforming to its specific signal molecule and, as a result, exposes a protein kinase (Kennedy). Protein kinases are the common intermediary agents in signal transduction.

A receptor is genetically determined and a cell does not respond to all the signals or stimuli it receives (Kennedy 2004). A ligand is the signaling molecule that binds the receptor and the receptor binds the ligand according to chemistry's law of mass action.

That specific receptor, called seven-spanning G. protein-linked receptor, lies at the beginning of a modular-type system of information transfer (Kennedy), which consists of a receptor that spans the plasma membrane, a G. protein, and an effector protein. G proteins are a binding location for the G. protein-linked receptor and a nucleotide called GDP/GTP (Kennedy). G proteins are active when bound to GTP and inactive when bounds to GDP.

Signal transduction is quite regulated. Cells must often revert to previous states and need to regulate the transduction mechanism (Kennedy 2004). And in order to remain responsive to stimuli, cells must quickly restore themselves into the previous state. Signaling pathways are like switches of sophisticated electrical systems where many complex cellular changes develop or are formed from the interactions of many simple switching systems (Kennedy).

The review of G. protein signaling was published almost two decades ago and central to this signaling process have been cell surface receptors (Morris and Malbon 1999). But since then, almost 20 heterotrimeric G. proteins and different groups of effect units, such as adenylyl cyclasses, that detail the physiological aspects of signaling through the given pathway, found continue to engage the interest and fascination of medical research. It is, therefore, the objective of this paper to attempt at grasping the fundamentals of the large and complex body of information already collected and still in progress on the subject. It will highlight the basic nature of G. protein-linked signaling and how physiological regulation occurs through particular mechanisms (Morris and Malbon).

DISCUSSION

Cells in multi-cellular organisms, like animals, need to communicate among themselves in directing and regulating growth, development and organization (Altruis Biomedical Network 2003). Such communication modes include secreting chemicals that signal to distant cells, display cell surface chemicals that influence other cells in direct physical contact, and directly through porous cellular points called gap junctions (Altruis Biomedical Network). Endocrine signaling demonstrates the first mode, wherein hormones are secreted in the bloodstream to distant target cells. Paracrine signaling illustrates the second mode, wherein local chemical mediators are secreted and act only on cells in the proximate environment. And synaptic signaling exhibits the third mode, wherein molecules are released by vesicles at those junctions called synapses. The molecules are neurotransmitters that spread out and act only...

Protein receptor molecules that are on or within the target cells bind to the hormone, paracrine or neurotransmitter and a response results, depending on the speed and selectivity of the delivered signal.
Hydrophilic molecules and hydrophobic prostaglandins induce cellular response through specific cell membrane receptors on the target cell (Altruis Biomedical Network 2003). These protein receptors, in turn, bind the signaling molecule, as if in strong affinity, and transduce signals that form or influence a certain cellular behavior. The response of the target cell derives from intracellular second messenger molecules, like cAMP, inositol phosphate and calcium. The three families of cell surface receptors, based on signal transduction mechanisms, are channel-linked receptors, catalytic receptors and G. protein-linked receptors. Channel-linked receptors are transmitter gated ion channels involved in fast synaptic signaling; catalytic receptors are similar to enzymes when activated by a specific ligand; and G. protein-linked receptors, when bound to a specific ligand, indirectly activate or inactivate a separate plasma membrane-bound enzyme or ion channel (Altruis Biomedical Network). This interaction between an enzyme or ion channel and a G. protein-linked receptor is mediated by a GTP. Chemical changes and events within the target cell and usually affect the concentration of secondary intracellular messengers, such as cAMP and inositol triphosphate. These intracellular messengers, in turn, affect the behavior of other intracellular proteins. The effects of these intracellular messengers are quickly reversed with the removal of the extra-cellular signal.

A protein-linked receptors are found in the cell membrane with an extracellular domain and an intracellular domain and the peptide chain always spanning the membrane (Lynn 2004). When binding to the extra-cellular domain, the hormone leads to a conformational change and causes the intracellular domain to activate G. proteins, which can raise the level of enzyme activity or decrease that in the secondary messenger systems (Lynn). There are non-G protein-linked surface receptors too. These have an intracellular domain, which is activated when the hormone binds to the extra-cellular domain. The intracellular domain either goes through an intrinsic enzyme activity itself or activates other enzymes inside the cell. These enzymes are often involved in kinase activity, such as the tyrosine-kinase receptor for insulin (Lynn).

Second messenger systems are activated when stimulated by the receptors and these systems amplify the signal (Lynn 2004). Only one hormone molecule can stimulate one receptor at a time and this stimulated receptor can produce many second messengers, every one of which can, in turn, stimulate other molecules within the cell. A single hormone molecule can, thus create a huge effect and this explains why hormone concentrations in the blood are quite low (Lynn). The main types of second messengers are cyclic adenosine monophosphate or cAMP, IP3 and diacylglycerol or DAG, and calcium. The enzyme adenylate cyclase produces cAMP. Subunits of G. proteins and others activated by phosphorylated enzyme-linked receptors can activate adenylate cyclase. In contrast, it is inhibited by inhibitory G. proteins. cAMP also activates other enzymes that further influence the expression of certain genes in the cell (Lynn).

IP3 and DAG derive from the PIP2 molecule phosphatidylinositor 4,5- bisphosphate by the enzyme phospholipase C (Lynn 2004). The enzyme is again stimulated by G. proteins and other proteins activated by phosphorylated enzyme-linked receptors. IP3 releases calcium from intracellular stores and, with DAG, can proceed to activate other enzymes, which in turn activate proteins that modify cell activity (Lynn).

Calcium can activate enzymes, such as protein kinase C. with DAG or bind to the calmodulin molecule, which in turn, can activate many other proteins, thus, produce a ripple effect and diverse cell activity and function (Lynn).

Cell communication, thus, happens through chemical signals and cellular receptors when there is direct contact of molecules between the surfaces of two cells or when a chemical signal is released and recognized by another proximate or distant cell (Department of Biology 2003). The circulatory systems take hormones to many locations and growth factors are released and act on proximate tissues. Ligands, on the other hand, are signals that bind cell surface receptors, such as insulin or pass into the cell and bind an internal receptor, such as steroid hormones (Department of Biology). Signal transduction is that cell activity to change in response to a receptor-ligand interaction, wherein the ligand is the primary messenger. With the binding, other molecules or second messengers develop within the target cell. These second messengers transmit the signal from one place to another, such as from the plasma membrane to the nucleus, and this series of changes occurs in the cell that can modify…