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 Figure 5. Diagram of the hormonal stimulation of different G-protein receptors and the up or downregulation of cAMP production. cAMP is shown activating protein kinase A (PKA), which regulates multiple cellular metabolic functions (7).
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AC acts as a signal transducer
within signal transduction from the exterior of a cell to the interior,
so any AC mutation or compound that alters normal AC function and/or regulation
will either cut the transduction pathway short or indefinitely perpetuate
the pathway. Also, since AC produces the second messenger cAMP, the normal
cellular metabolic functions, such as enzyme activity, gene-expression
patterns, and membrane excitability, regulated by cAMP will be altered.
cAMP regulates a wide variety of cellular functions by activating forms
of protein kinase (Fig. 5).
The functions affected depend upon the hormonal stimulus and the hormone’s target tissue. For example, when the hormone adrenaline binds to G-protein associated receptors in cells of the heart, cAMP is upregulated by the activation of AC. cAMP then stimulates an increase in heart rate and contraction strength. The same hormonal stimulus targets muscle and fat cells, but causes different responses. In muscle, cAMP induces glycogen breakdown, and in fat cells, cAMP induces lypolysis. Thus, the abnormal production or regulation of cAMP could have major detrimental effects on these metabolic processes. G-proteins are regulated by numerous other hormones including glucagon, secretin, and parathyroid, among others, which all confer induction of separate signal transduction cascades. However, all theses cascades are sustained by only a few forms of AC within an organism, making AC’s function vitally important in cellular metabolic function. This makes implications of disease and metabolic abnormalities associated with AC dysfunction due to mutations or disease almost endless. Examples of disease caused by AC dysfunction or dysfunction in AC regulation include whooping cough and malignant hyperthermia. Whooping cough is caused by the pertussis toxin produced by the bacterium Bordetella pertussis. Ultimately pertussis toxin blocks inhibition of AC by Gia leading to an overproduction of cAMP in multiple tissues. This overproduction disrupts normal functions regulated by cAMP, conferring the diseased state, in this case, whooping cough. Malignant hyperthermia (MH) is an example of the effects of high AC activity. MH results from a high cAMP concentration in skeletal muscle that accumulates as a result of abnormally elevated AC activity. (see My Adenylyl Cyclase Minireview for more detail and referencing) |