In addition to activation by type I receptors which are directly coupled to ion channels and by a-units derived from some G proteins such as G s, ion channels can also be activated by phosphorylation reactions. For example, the calcium channels regulated directly by G s are in addition phosphorylated by protein kinase A, which leads to further increases in their functional activity. Protein kinases may open channels which are closed at the resting membrane potential, an action similar to that of a transmitter on a directly gated ion channel. Kinases activated by second messengers may also close channels that are open at the resting potential, or close non-gated potassium channels which contribute to the resting potential by leakage. Closure of these channels has a depolarizing effect, increasing the excitability of the neurone and overriding its tendency to accommodate during prolonged stimulation. An example of such an effect is the closure of calcium-stimulated potassium channels by noradrenaline acting through cAMP in hippocampal neurones, leading to a longer period of firing in response to glutamate. Some ion channels may also be modulated directly by second messengers such as cAMP or cGMP without requiring protein phosphorylation.
Class I receptors may also be regulated by phosphorylation. An example is the nicotinic acetylcholine receptor, which is phosphorylated on its a-subunit by protein kinase C, on its b-subunit by tyrosine-specific kinases, on its g-subunit by protein kinase A and tyrosine-specific kinases, and on its d-subunit by all three kinases. The cAMP-dependent phosphorylation of the b- and g-subunits increases the rate at which the receptor is desensitized. This is an example of one of the multiple feedback regulations which serve to achieve fine tuning of cellular responses.
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