The specific slow afterhyperpolarization inhibitor UCL2077 is a subtype-selective blocker of the epilepsy associated KCNQ channels.

Mutations in members of the KCNQ channel family underlie multiple diseases affecting the nervous and cardiovascular systems. Despite their clinical relevance, research into these channels is limited by the lack of subtype-selective inhibitors, making it difficult to differentiate the physiological function of each family member in vivo. We have proposed that KCNQ channels might partially underlie the calcium-activated slow afterhyperpolarization (sAHP), a neuronal conductance whose molecular components are uncertain.

The KCNQ5 potassium channel mediates a component of the afterhyperpolarization current in mouse hippocampus.

Mutations in KCNQ2 and KCNQ3 voltage-gated potassium channels lead to neonatal epilepsy as a consequence of their key role in regulating neuronal excitability. Previous studies in the brain have focused primarily on these KCNQ family members, which contribute to M-currents and afterhyperpolarization conductances in multiple brain areas. In contrast, the function of KCNQ5 (Kv7.

Contribution of KCNQ2 and KCNQ3 to the medium and slow afterhyperpolarization currents.

Benign familial neonatal convulsion (BNFC) is a neurological disorder caused by mutations in the potassium channel genes KCNQ2 and KCNQ3, which are thought to contribute to the medium afterhyperpolarization (mAHP). Despite their importance in normal brain function, it is unknown whether they invariably function as heteromeric complexes. Here, we examined the contribution of KCNQ3 and KCNQ2 in mediating the apamin-insensitive mAHP current (ImAHP) in hippocampus.

Glutamate transporters: confining runaway excitation by shaping synaptic transmission.

Traditionally, glutamate transporters have been viewed as membrane proteins that harness the electrochemical gradient to slowly transport glutamate from the extracellular space into glial cells. However, recent studies have shown that glutamate transporters on glial and neuronal membranes also rapidly bind released glutamate to shape synaptic transmission. In this Review, we summarize the properties of glutamate transporters that influence synaptic transmission and are subject to regulation and plasticity.

Hippocalcin gates the calcium activation of the slow afterhyperpolarization in hippocampal pyramidal cells.

In the brain, calcium influx following a train of action potentials activates potassium channels that mediate a slow afterhyperpolarization current (I(sAHP)). The key steps between calcium influx and potassium channel activation remain unknown. Here we report that the key intermediate between calcium and the sAHP channels is the diffusible calcium sensor hippocalcin.

Arc/Arg3.1: linking gene expression to synaptic plasticity and memory.

Arc/Arg3.1 is an effector immediate-early gene implicated in the consolidation of memories. Although cloned a decade ago, the physiological role of Arc/Arg3.

Intrinsic kinetics determine the time course of neuronal synaptic transporter currents.

Efficient clearance of synaptically released glutamate from the extracellular space is an absolute requirement for maintaining information processing in the central nervous system. In the cerebellum, clearance of glutamate relies on uptake by Bergmann glial cells and Purkinje cells (PCs). Uptake by PCs can be monitored by recording the synaptic transport current (STC) mediated by the PC-specific transporter excitatory amino acid transporter 4 (EAAT4).

Molecular constituents of neuronal AMPA receptors.

Dynamic regulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) underlies aspects of synaptic plasticity. Although numerous AMPAR-interacting proteins have been identified, their quantitative and relative contributions to native AMPAR complexes remain unclear. Here, we quantitated protein interactions with neuronal AMPARs by immunoprecipitation from brain extracts.

Fluorometric measurements of conformational changes in glutamate transporters.

Glutamate transporters remove glutamate from the synaptic cleft to maintain efficient synaptic communication between neurons and to prevent extracellular glutamate concentrations from reaching neurotoxic levels (1). It is thought that glutamate transporters mediate glutamate transport through a reaction cycle with conformational changes between the two major access states that alternatively expose glutamate-binding sites to the extracellular or to the intracellular solution. However, there is no direct real-time evidence for the conformational changes predicted to occur during the transport cycle.

Comparison of coupled and uncoupled currents during glutamate uptake by GLT-1 transporters.

The transport of glutamate across the plasma membrane is coupled to the movement of cations (Na+, K+, and H+) that are necessary for glutamate uptake and transporter cycling as well as anions that are uncoupled from the flux of glutamate. Although the relationship between these coupled (stoichiometric) and uncoupled (anion) transporter currents is poorly understood, transporter-associated anion currents often are used to monitor transporter activity. To define the kinetic relationship between these two components, we have recorded transporter currents associated with stoichiometric and anion charge movements occurring in response to the rapid application of l-glutamate to outside-out patches from human embryonic kidney cells expressing GLT-1 transporters.