Second messengers

The binding of ligands to several receptors leads to a short-lived raise in the concentration  of certain intracellular  signaling   molecules known as  second

                     Figure:  Cycling of the GTPase switch proteins between the active and inactive forms

messengers.  The hormone or ligand can be considered as the best messenger. The  major  second  messengers  are 3',5'-cyclic  GMP 2 (cGMP),   3',5'-cyclic  AMP   or cAMP,  inositol  1,4,5-trisphosphate (IP3), 1,2-diacylglycerol (DAG)  and Ca²⁺ . The elevation in the stages of one or other of these second messengers then leads to a rapid alteration in cellular function.

 cGMP and cAMP are derived from ATP and GTP through the actions of adenylyl cyclase and guanylyl  cyclase, respectively.  For instance,  the action of glucagon  and epinephrine on  glycogen  metabolism  is  mediated  by  the  second messenger  cAMP that in turn activates the cAMP-dependent protein kinase, protein  kinase  A. cAMP and cGMP  are short-lived  as they are rapidly broken down through phosphodiesterases.

IP3 and DAG are derived from the membrane lipid phosphatidylinositol 4 or 5- bisphosphate which  is  a  phosphorylated   derivative  of  phosphatidylinositol  through  the  action  of phospholipase  C that  is also  located  in the plasma  membrane  and like  adenylyl  cyclase is  activated  through  G  proteins  via GPCRs. One of the major actions of the polar IP3  is to diffuse by the cytosol  and  interact  with  Ca²⁺ channels  in  the  membrane  of  the  ER is causing the release of stored Ca²⁺ ions which in turn mediate various cellular responses.  An  DAG  produced  through  the  hydrolysis  of phosphatidylinositol 4,5- bisphosphate,   along  with  Ca²⁺ ions  released  from  the  ER  make active  protein kinase C a membrane-bound serine or threonine protein kinase which phosphorylates various target proteins over leading to alterations  in a variety of cellular processes.

Calcium ions several extracellular signals induce a raise in the level of Ca²⁺ ions in the cytosol.  For instance, in muscle cells, Ca²⁺switches contraction. The concentration of Ca²⁺in the cytosol is usually kept very low around.  0.1 μM, whereas it’s concentration in the extracellular fluid and in the lumen of the ER is high around.  1 μM.  Thus there is a gradient of Ca²⁺ ions across the

                 Figure:  Generation of the intracellular second messengers inositol 1,4,5-trisphosphate (IP3), 1,2-diacylglycerol  (DAG) and Ca²⁺ .

plasma  membrane  and ER membrane,  like which when  Ca²⁺ channels  in these membranes are triggered to open, Ca²⁺ ions rapidly ?ow into the cytosol, raising the  Ca²⁺ concentration  through  10–20-fold  and  switching  Ca²⁺-responsive  proteins inside the cell. There are three main types of Ca²⁺ channel:  voltage-dependent Ca²⁺ channels  in  the  plasma  membrane  which  open  in  response  to  membrane 2 epolarization,   for  instance   in  nerve   cells;  IP3-gated   Ca²⁺   -channels in the ER and ryanodine receptors so called because they are  inhibited   by  the  plant  alkaloid   ryanodine that  release   Ca²⁺ from  the sarcoplasmic  reticulum  in muscle  cells or the ER of other cells. Ca²⁺     pumps, such as the Ca²⁺ -ATPase, in the ER and plasma membrane help to maintain the low concentration of Ca²⁺ ions in the cytosol of resting cells. Ca²⁺   - binding proteins serve as transducers of the cytosolic Ca²⁺      signal. These Ca²⁺   - binding  proteins  include  troponin  C  in  skeletal  muscle  (see  Topic  A3)  and calmodulin a ubiquitous protein establish in all eukaryotic cells. The Calmodulin methods as a multipurpose   intracellular Ca²⁺ receptor, mediating   many Ca²⁺- regulated procedure   and undergoes   a conformational   change upon binding Ca^2+. The  activated  calmodulin  can  then  bind  to a number  of different  target proteins,  including  a  family  of Ca²⁺  or calmodulin-dependent  protein  kinases (CaM kinases) which then phosphorylate  serines or threonines on other proteins.