Biochemical Mediation of Adrenergic Responses

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Chapter: Essential pharmacology : Adrenergic System and Drugs

The β actions are mediated through cAMP (see Fig. 4.6). Adr activates membrane bound enzyme adenylyl cyclase through a regulatory protein Gs → ATP is broken down to cAMP at the inner face. This in turn phosphorylates a number of intracellular cAMPdependent protein kinases and initiates a series of reactions:


BIOCHEMICAL MEDIATION OF ADRENERGIC RESPONSES

 

 β Actions

  

The β actions are mediated through cAMP. Adr activates membrane bound enzyme adenylyl cyclase through a regulatory protein Gs ATP is broken down to cAMP at the inner face. This in turn phosphorylates a number of intracellular cAMPdependent protein kinases and initiates a series of reactions:

 

In liver and muscle, glycogen phosphorylase is activated causing glycogenolysis while glycogen synthetase is inhibited. Both actions result in hyperglycaemia and hyperlactacidemia. Neoglucogenesis in liver adds to the response.

 

K+ is first released from liver hyperkalaemia; followed by more prolonged hypokalaemia due to K+ uptake in muscle and later in liver itself.

 

In adipose tissue, triglyceride lipase is activated increased plasma free fatty acids. Increased O2 consumption and heat production result primarily by action on brown adipose tissue, which has predominant β3 receptors.

 

In heart, proteins like troponin and phospholamban are phosphorylated. The former results in increased interaction with Ca2+ at the myofilaments increased force of contraction; the latter causes sequestration of Ca2+ by sarcoplasmic reticulum more rapid relaxation. The activated protein Gs, in addition, interacts directly with the Ca2+ channels in the membrane promoting influx of Ca2+ which reinforces the positive inotropic action exerted through cAMP.

 

In the gut and bronchial muscle, relaxation (accompanied with hyperpolarization) is induced, but the intermediate steps have not been clearly delineated.

 

In pancreatic islets activation of β2 receptors on α cells increases glucagon secretion, and that on β cells increases insulin secretion, both by raising intracellular cAMP. However, augmentation of insulin secretion is weak.

 

α Actions

 

The mediation of α actions is varied and less well defined.

 

In smooth muscles (including vascular) that are contracted through α1 receptors, the activated Gprotein increases IP3/DAG production mobilization of Ca2+ from intracellular organelle activation of calmodulin dependent myosin light chain kinase phosphorylation of myosin contraction. The vasoconstrictor α2 receptors probably enhance Ca2+ influx without utilizing IP3.

 

The prejunctional α2 receptor appears to inhibit neuronal Ca2+ channels and also limit the intracellular availability of Ca2+ by decreasing cAMP production. Transmitter (NA) release is consequently diminished. Hyperpolarization through activation of K+ channels may also occur.

 

In the gut, α2 receptor activation hyperpolarizes the cholinergic neurone decreased release of ACh reduced tone; whereas α1 receptors located directly on the smooth

muscle   cell    increase   K+     efflux       hyperpolarization relaxation.

 

In pancreatic β cells, stimulation of α2 receptors reduces the formation of cAMP decreased insulin release.

 

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