Calcium cAMP pathway interaction

This can be illustrated by known interactions between the cAMP and Ca2+ pathways. A first messenger that initially activates the cAMP pathway would be expected to exert secondary effects on the Ca2+ pathway at many levels via phosphorylation by PKA. First, Ca2+ channels and the inositol trisphosphate (IP3) receptor will be phosphorylated by PKA to modulate intracellular concentrations of Ca2+. Second, phospholipase C (PLC) is a substrate for PKA, and its phosphorylation modulates intracellular calcium concentrations, via the generation of IP3) as well as the activity of PKC, via the generation of DAG, and several types of CAMK. Similarly, the Ca2+ pathway exerts potent effects on the cAMP pathway, for example, by activating or inhibiting the various forms of adenylyl cyclase expressed in mammalian tissues (see Ch. 21). 

The first experiments utilizing an endocannabinoid to affect ion channel activity demonstrated the inhibition of N- and Q-type voltage-dependent caldum channels (VDCC) in cell lines transfected with the cDNA for CBj receptors or containing the native protein (Mackie et al., 1993 Mackie et al., 1995). The inhibition produced by AEA was blocked by permssis toxin and not because of the activation of the cAMP pathway (Mackie et al., 1993). The effect observed was likely the result of a direct interaction of G subunits with calcium channels (Ikeda, 19%). 

PKG and PKA are serine/threonine kinases which become activated by agonists that evoke an increase in either cGMP levels or cAMP levels, respectively. Butt et al. (2000) recently reported that activation of PKG and PKA induced serine phosphorylation of eNOS rendering the enzyme Ca " -independent [39]. In this study eNOS was found to be phosphorylated on serine 1177, serine 633 and threonine 495 allowing for enzyme activation in the absence of calcium-calmodulin. Moreover as there are reports that PKA can activate Akt/PKB via a PI3-kinase dependent pathway [43], various intracellular kinase cascades may interact with one another leading to the control of eNOS activity via phosphorylation. 

It has now been established by studies of numerous tissues that the interaction of all members of the Nk receptor family with appropriate ligands results in G protein-linked activation of phospholipase C and phos-phoinositol turnover with increased synthesis of inositol triphosphate (IPs) and consequent increases in levels of intracellular calcium (Nakanishi et al., 1993). This activation occurs via a pertussis toxin-insensitive pathway and probably involves the Gq/11 subfamily of Ga proteins (Kwatra et al., 1993). Activation of transfected tachykinin receptors in CHO cells can also result in the generation of cAMP (Nakajima et al., 1992 Wiener, 1993). 

The H2 receptor is a 359-amino-acid protein in humans. It has some features similar to the Hi protein (e.g., N-terminal glycosylation sites) and phosphorylation sites in the C-terminal. An aspartic acid residue in the third transmembrane loop appears to be critical to agonist and antagonist binding, and threonine/aspartate and tyrosine/aspartate couples in the fifth transmembrane domain appear to be important for interaction of the imidazole part of the histamine molecule. It is positively coupled via Gas to activate adenylyl cyclase for synthesis of cyclic adenosine monophosphate (cAMP) as a second messenger. In some systems, it is coupled through Gq proteins to stimulate phospholipase C. It appears in some cells that other processes, such as breakdown of phosphoinositides, control of intracellular calcium ion levels, and phospholipase A2 activity, can be regulated by other cAMP-independent pathways. 

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