Various other G proteins are also known, eg, Gi (i for inhibitory, as s in Gs stands for stimulatory),

stimulaled protein kinase A phosyhorylates the corresponding enzyme (phosphorylation of enzyme protein either inhibits or stimulates Ihe enzyme, depending upon the nature of Ihe enzyme) the corresponding biochemical reaction is either depressed or stimulated biological effect. What are the chemical events that occur between the combination of R and the L (the 1st messenger) and production of the cAMP (the 2nd messenger) ? Answer is as follows: recall, the R has two domains (i) the ligand bin ding site and (ii) the active site. Also recall, that the RLC formation occurs in the ligand binding site. Once the RLC has formed, the chain of events will be, RLC (ligand binding site) the active site now recognizes that the L of the RLC is an agonist (not antagonist) RLC now stimulates a protein, called Gs (G slimulatory) prolein, situaled close to the RLC and situated within the membrane (fig.6.1.1). Gs is now activated he activated Gs now stimulates an enzyme, adenyl cyclase (also called adenylate cyclase, but adenyl cyclase is more popular), abbreviated AC, also situated in the membrane (fig. 6.1.1) and hence called membrane bound AC AC now acts on ATP to form cAMP cAMP stimulates protein kinase A stimulated protein kinase A phosphorylates enzyme proteins the enzyme(s) is (are) either stimulated or inhibited allered metabolism = biological effect (see also below) More serious readers can note that the Gs protein, when inac tive, remains bound with GDP (guanosine diphosphate) but when the GDP is replaced by GTP (guanosine triphosphate) the Gs becomes active (fig. 6.1.3). The active protein kinase A can, instead of phosphorylating an enzyme, cause opening up of channels present in the cell membrane (fig. 1.1. 2) -> ions enter or leave the ICF. This, therefore, is another biological effect of cAMP. Components of hormone sensitive adenyl cyclase Note (fig. 6.1.1) that the formation of cAMP from ATP requires three components, (i) receptor (ii) Gs prolem (iii) adenyl cyclase. Gs protein is called the coupling unit (as it couples the R with the AC). Adenyl cyclase is called the catalytic cyclase (abbr. C). The three components, viz the R, the coupling unit and the C taken together, is called the membrane bound (hormone sensitive) adenyl cyclase system. Fig. 6.1.1. Mechanism of action at molecular level, of hormones which ad by generating cAMP. For his works on cAMP and for establishing the concept of sec-ond messenger Earl Sutherland was awarded Nobel Prize in 1970. Degradation of cAMP (fig. 6.1.2) The enzyme phosphodiesterase (PDE) degrades the cAMP to 5' AMP. There are several varieties of phosphodiesterases (PDEs). The drugs caffeine and theophylline oppose the PDEs and thus prolong the action of cAMP. Gr. 8. Hormones (fig. 6.1.4) The hormones of this group bind with the R in the target cell membrane and RLC is formed RLC now activates a G protein (present in the membrane) called Gp prolein. Gp protein thus, here, is the coupling unit Gp protein now stimulates a catalytic unit named phospholipase C (PLC) Phospholipase C now hydrolyses phosphalidyl inositol diphosphate (PIP2) forming mositol triphosphate (IP3) and diacylglycerol (DAG). Both IP3 & DAG are 2nd messengers. DAG now activates protein kinase C. Prolein kinase C is an intracellular enzyme. Also IP3 is formed within the cell membrane —> diffuses into the cytosol. Subsequent events are as follows: Fig. 6.1.4. IP3, DAG & Ca++ are 2nd messengers Role of released Ca++ ions Concentration of Ca++ is high in the ECF but very low in the ICF. However, normally the Ca++ ions cannot enter the cell. But when the chemical signal like angiotensin II acts and the membrane bound PLC becomes active, IP3 is formed within the cell membrane diffuses inlo the cylosol triggers off release of Ca++from endoplasmic reticulum. Ca++ entry (from the ECF) into the ICF is also facilitated. The free Ca++ ions, thus available within the cylosol, now bind with a prolein called calmodulin to form what is known as calcium calmodulin complex. This calcium calmodulin complex (C - Ca++ complex) now activates many processes that culminate in various biological effects, like, (i) contraction of muscle, (ii) synaptic transmission, and (iii) glycogenolysis. [ NB. Calmodulin is closely related to the contractile protein in the muscle, troponin C, see figs 5.1.7 and 5.2.1 ]. The G proteins Thus, we have come across with two types of G proteins, viz, (i) Gs and (ii) the Gp proteins. They are coupling units, present in the cell membrane and are also called 'nucleotide regulatory proteins', (because they control the formation of nucleotides like cAMP). They link the RLC with the membrane bound catalytic units like adenyl cyclase phosphohpase C (PLC). Various other G proteins are also known, eg, Gi (i for inhibitory, as s in Gs stands for stimulatory), Gt and Gk. They will however be not described in this text. The 2nd messengers cAMP, Ca++, DAG, IP3 have been described above. Other well known 2nd messengers include cGMP (involved in the action of ANP, atrial natrinretic protem which is a hormone released from the atrium and broadly speaking, opposes the action of renin angiotensin axis). Gr C Hormones Insulin and the various growth factors, like, (i) IGF (insulin like growth factor), (ii) EGF (epidermal growth factor), (iii) PDGF (plalelet derived growth factor), as well as vasopressin fall in this calegory. These hormones bind with_the_R in the_membrane to form the RLC, but no 2nd messenger is formed, or at least, no 2nd messenger is known to be fo