Receptors

Question 1

Ionotropic vs metabotropic

Answer 1

• ionotropic receptors: function as ion channels
  
  • gated by neurotransmitters and conduct
    ion passage through the membrane
  • fast-acting
• metabotropic receptors
  
  • activated by NT
  • trigger intracellular signaling cascades t .
    o regulate ion channel conductance —>
    modulate membrane potential indirectly ( .
    the ions themselves do not go through)
  • operate over longer time scale
  • no concentrated on postsynaptic
    membrane and are termed ‘extrasynaptic’
• many NT have both ionotropic and metabotropic receptors

Question 2

AMPA and NMDA GLU receptors are activated by GLU under different conditions

Answer 2

• ionotropic GLU receptors are responsible for the fast action of GLU, the main excitatory NT
• virtually all neurons whether they are excitatory, inhibitory, or modulatory express iontropic GLU receptors
• cation channels that do not select between Na+ and K+
• GLU binding to ionotropic GluR causes an inward current called excitatory postsynaptic current —> more positive ions flow into cell than out
• inward current cases EPSP
• ionotropic GluR have been divided into three subtypes named after their selective responses to three agonists: AMPA, kainate, NMDA
  
  • molecular cloning of these receptors showed that they are each encoded by distinct gene subfamilies
  • AMPA and kainate receptors are more similar, therefore grouped together into non-NMDA receptors
  • NMDA has distinctive properties

Question 3

AMPA

Answer 3

• fast glutamate-gated ion channels that conduct Na+ and K+ (some are also permeable to Ca2+)
• mediate synaptic transmission at the GLU synapses when the postsynaptic neuron is near the resting potential
• AMPA receptor opening causes net influx of positively charged ions, resulting in depolarization of postsynaptic neuron

Question 4

NMDA

Answer 4

• unusual property: gated by glutamate AND influenced by membrane potential, require glycine as co-agonist
• Mg2+ blocks entrance of NMDA receptor at negative potentials —> channel remains closed during GLU binding
• depolarization of the postsynaptic membrane relieves the Mg2+ block
• acts as a coincidence detector: opens only in response to concurrent presynaptic GLU release AND postsynaptic polarization
• important for synaptic plasticity, learning, and activity-dependent wiring of the nervous system
• once opened, NMDA receptors have high Ca2+ conductance

—> AMPA provides initial depolarization to release the Mg2+ in NMDA receptors —> NMDA contribute additional depolarization

Question 5

How are GLU receptor subunits arranged and how does ligand binding trigger channel opening?

Answer 5

• differences in subunit composition of both receptors has important consequences
  
  • e.g. most AMPA receptors contain GluA2
    subunit, of which most are impermeable
    to Ca2+
  • AMPA receptors that don’t have GluA2
    are permeable to Ca2+
  • NMDA receptors contain variations of
    GluN2 which has functional implications f .
    or channel conductance, binding to
    postsynaptic scaffolding proteins, and c .
    ytoplasmic signaling properties

—> combinations of different subunits allow both receptor types to have a rich repertoire of functional and regulatory properties

Question 6

Ionotropic GABA and glycine receptors are Cl- channels that mediate inhibition

Answer 6

• GABA leads to membrane potential changes called postsynaptic current and inhibitory postsynaptic potential (IPSP)
• glycine receptors or GABA(A) receptors
• many pharmoacological agents act on GABA(A) receptors such as anti-epilepsy, anti-anxiety, and sleep-promoting drgs

Question 7

How does increase of CL- conductance from open GABA(A) receptor channels cause inhibition?

Answer 7

• Cl- influx causes a small hyperpolarization
• if the neuron also receives simultaneously excitatory input which produces EPSP, the relatively depolarized potential increases the driving force for CL- influx —> increases outward current which encounters EPSP producing inward current —> difficult for neuron to fire
• noteworthy: in developing neurons, intracellular Cl- is already high because their Cl- exchangers are not yet fully expressed —> increase in Cl- results in Cl- efflux causing depolarization to exceed threshold for AP —> under these circumstances, GABA can act as an excitatory NT

Question 8

All metabotropic NT receptors trigger G protein cascades

Answer 8

• ACh, GLU, and GABA all bind to their own metabotropic receptors
• also receptors for DA, norepinephrine, 5HT, ATP, adenosin and all neuropeptides as well as sensory reeptors
• g-protein coupled receptors are crucial for neuronal communication, for responding to external stimuli, and for regulating many other physiological processes
• many pharmaceutical drugs target GPCRs, demonstrating their importance to human physiology and health