Biochemistry Online: An Approach Based on Chemical Logic

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Learning Goals/Objectives for Chapter 9C:
After class and this reading, students will be able to

  • define kinases and phosphatases and their role in signal transduction
  • define primary and secondary messengers and give specific examples of each
  • describe the role of G proteins in coupling ligand induced conformational changes in the bound receptor to activation of specific effector proteins such as adenylate cyclase and phospholipase
  • differentiate between kinases activated by second messengers and those activated by primary messengers (ligand-gated receptor Tyr kinases)
  • describe the structural characteristics of G protein coupled serpentine receptors and ligand gated receptor tyrosine kinases
  • draw a diagram showing the general features of kinases mediated signal transduction pathways that lead to activation of gene expression
  • differentiate between neuron responses mediated by neurotransmitters on binding gated receptor/ion channels compares to G-protein coupled receptors

Estonian Translation by Anna Galovich

C13.  Metabotropic Neural Receptors

You may have noticed above that some signaling molecules, whose effects are regulated by kinases (β-adrenergic and some olfactory signals by PKA and acetylcholine by PKC for example), are neurotransmitters.   In the previous chapter section, we discussed how neurotransmitters can act as signals to open ion-specific, ligand-gated membrane channels, which change the transmembrane potential.  In other words, the neurotransmitters gate the channels directly.   Typical examples of channels directly gated by neurotransmitters are the acetylcholine receptor in neuromuscular junctions and the Glu, Gly, and GABA receptors in the central nervous system.  These receptors are multimeric proteins.  Receptors with direct gating of ion flow are fast, with activities that last milliseconds, and are used in eliciting behavioral responses.

However, ion channels can also be gated indirectly when the neurotransmitter binds to its receptor and leads to events which open an ion channel that is distinct from the receptor.   In this case, the occupied receptor communicates to an ion channel indirectly through a G protein.  Example of this indirect gating of ion channels include the serotonin, adrenergic, and dopamine receptors in the brain.  These receptors are classic single protein serpentine receptors with 7 transmembrane helices, and intracellular domains that can interact with G proteins as described above to increase second messenger levels (cAMP, DAG) in the neuron.   These can either activate kinases in the cell, which phosphorylate ion channels to either open or close them, or can bind directly to the channel and modulate its activity through an allosteric conformational change.  In some cases the G protein directly acts on the ion channel.   These different ways are described below.  In contrast to direct gating, receptors that indirectly gate ion channels have activities that are slow and last seconds to minutes.   These receptors are usually involved in modulating behavior by changing the excitability of neurons and the strength of neural connections, hence modulating learning and memory.  These changes can occur in many ways, summarized below and in the following link:

Figure:  Neurotransmission:  Gating through G Linked Receptors

Animations: Direct and Indirect Neurotransmitter Action

Phosphorylating ion channels: Receptors that act through a second messenger system can change ion channel activity by activating kinases which phosphorylate the channels.  This may:

Gα interaction with ion channels: 

Second messenger interaction with ion channels:  

Second messenger effects on proteins other than ion channels (usually different receptors): 

Second messenger regulates gene expression:


Caffeine clearly produces a state of arousal in the central nervous system.  High levels appear to block the binding of an inhibitory neurotransmitter, adenosine, to the A2A adenosine receptor.  In the absence of caffeine, adenosine levels rise during the day, which promotes interaction with its receptor, leading to increasing sleepiness and lack of concentration.   When adenosine binds normally to its receptors, it activates the adenylate cyclase cascade, which activates PKA, leading to changes in phosphorylation state of many proteins inside the cell, including protein phosphatase (2A).  These changes inhibit neural firing.  Caffeine blocks these changes. 

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