Jaarboek no. 89. 2010/2011 - Koninklijke Maatschappij voor ...

an inhibitory interneuron. Both the localization of
the FHM protein and the nature of the defect will
determine the net effect of the mutation on overall
brain activity.
A. FHM1
CaV2.1 is depicted at the presynaptic terminal of
excitable neurons, where a gain of function will
increase transmitter release. It bears mentioning,
however, that this same channel is also present at
Natuurkundige voordrachten I Nieuwe reeks 89
Migraine: de ontrafeling van een complexe ziekte
Figure 4
Cartoon depicting a glutamatergic synapse in the central nervous system and the functional roles of proteins
encoded by the FHM1, FHM2, and FHM3 genes. CaV2.1 calcium channels are located in the presynaptic terminal of
excitatory and inhibitory neurons. In response to an invading action potential, these channels gate, allowing Ca2+ to
enter and triggering vesicle fusion and glutamate release into the synaptic cleft. K + in the synaptic cleft is removed
in part by the action of the Na + /K + -ATPase located at the surface of glial cells (astrocytes). Removing extracellular K +
serves to dampen neuronal excitability and generates a Na + gradient, which drives uptake of glutamate from the
cleft by transporters, for example, EAAT1. Lastly, the NaV1.1 voltage-gated sodium channel is expressed in inhibitory
interneurons, where they serve to initiate and propagate action potentials. Gain-of-function mutations in CaV2.1 and
loss-of-function mutations in the ATPase and NaV1.1 will each lead to a net effect of increased general excitability.
nerve terminals of inhibitory neurons, where the
FHM1 mutation may serve to dampen excitability,
perhaps partially protecting the brain during an episodic
attack.
B. FHM2
Early in development, the Na + /K + -ATPase α2 subunit
is expressed in neurons. However, in adult brain,
expression is predominantly in glial cells, which
play a critical role in removing transmitters and K +
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