KCND2

Voltage-gated potassium (Kv) channels represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume. Four sequence-related potassium channel genes - shaker, shaw, shab, and shal - have been identified in Drosophila, and each has been shown to have human homolog(s). This gene encodes a member of the potassium channel, voltage-gated, shal-related subfamily, members of which form voltage-activated A-type potassium ion channels and are prominent in the repolarization phase of the action potential. This member mediates a rapidly inactivating, A-type outward potassium current which is not under the control of the N terminus as it is in Shaker channels. [provided by RefSeq, Jul 2008]

Potassium Voltage-Gated Channel Subfamily D Member 2

Voltage-gated potassium channel that mediates transmembrane potassium transport in excitable membranes, primarily in the brain. Mediates the major part of the dendritic A-type current I(SA) in brain neurons (By similarity).
This current is activated at membrane potentials that are below the threshold for action potentials. It regulates neuronal excitability, prolongs the latency before the first spike in a series of action potentials, regulates the frequency of repetitive action potential firing, shortens the duration of action potentials and regulates the back-propagation of action potentials from the neuronal cell body to the dendrites. Contributes to the regulation of the circadian rhythm of action potential firing in suprachiasmatic nucleus neurons, which regulates the circadian rhythm of locomotor activity (By similarity).
Functions downstream of the metabotropic glutamate receptor GRM5 and plays a role in neuronal excitability and in nociception mediated by activation of GRM5 (By similarity).
Mediates the transient outward current I(to) in rodent heart left ventricle apex cells, but not in human heart, where this current is mediated by another family member. Forms tetrameric potassium-selective channels through which potassium ions pass in accordance with their electrochemical gradient (PubMed:10551270, PubMed:15454437, PubMed:14695263, PubMed:14623880, PubMed:14980201, PubMed:16934482, PubMed:24811166, PubMed:24501278).
The channel alternates between opened and closed conformations in response to the voltage difference across the membrane (PubMed:11507158).
Can form functional homotetrameric channels and heterotetrameric channels that contain variable proportions of KCND2 and KCND3; channel properties depend on the type of pore-forming alpha subunits that are part of the channel. In vivo, membranes probably contain a mixture of heteromeric potassium channel complexes. Interaction with specific isoforms of the regulatory subunits KCNIP1, KCNIP2, KCNIP3 or KCNIP4 strongly increases expression at the cell surface and thereby increases channel activity; it modulates the kinetics of channel activation and inactivation, shifts the threshold for channel activation to more negative voltage values, shifts the threshold for inactivation to less negative voltages and accelerates recovery after inactivation (PubMed:15454437, PubMed:14623880, PubMed:14980201, PubMed:19171772, PubMed:24501278, PubMed:24811166).
Likewise, interaction with DPP6 or DPP10 promotes expression at the cell membrane and regulates both channel characteristics and activity (By similarity).

Action potentialManual Assertion Based On ExperimentTAS:UniProtKB
Cellular response to hypoxiaISS:UniProtKB
Chemical synaptic transmissionManual Assertion Based On ExperimentTAS:UniProtKB
Locomotor rhythmIEA:Ensembl
Neuronal action potentialIEA:Ensembl
Potassium ion transmembrane transportManual Assertion Based On ExperimentIDA:UniProtKB
Protein homooligomerizationIEA:InterPro
Regulation of ion transmembrane transportIEA:UniProtKB-KW
Sensory perception of painIEA:Ensembl

Cell membrane; Cell projection, dendrite; Cell junction, synapse; Perikaryon; Cell junction, synapse, postsynaptic cell membrane; Cell projection, dendritic spine; Cell junction. In neurons, primarily detected on dendrites, dendritic spines and on the neuron cell body, but not on axons. Localized preferentially at the dendrites of pyramidal cells in the hippocampus CA1 layer. Detected at GABAergic synapses. Detected at cell junctions that are distinct from synaptic cell contacts. Detected in lipid rafts. Detected primarily at the endoplasmic reticulum or Golgi when expressed by itself (PubMed:15454437).
Interaction with KCNIP1, KCNIP2, KCNIP3 or KCNIP4 promotes expression at the cell membrane (PubMed:15454437, PubMed:24811166).
Interaction with DPP6 or DPP10 promotes expression at the cell membrane (By similarity).
Internalized from the cell membrane by clathrin-dependent endocytosis in response to activation of AMPA-selective glutamate receptors and PKA-mediated phosphorylation at Ser-552. Redistributed from dendritic spines to the main dendritic shaft in response to activation of AMPA-selective glutamate receptors and activation of PKA (By similarity).

KNCD2 mutations have been found in a family with autism and epilepsy and may play a role in disease pathogenesis. Autism is a complex multifactorial, pervasive developmental disorder characterized by impairments in reciprocal social interaction and communication, restricted and stereotyped patterns of interests and activities, and the presence of developmental abnormalities by 3 years of age. Epilepsy is characterized by paroxysmal transient disturbances of the electrical activity of the brain that may be manifested as episodic impairment or loss of consciousness, abnormal motor phenomena, psychic or sensory disturbances, or perturbation of the autonomic nervous system.
A KCND2 mutation leading to the production of a C-terminally truncated protein has been identified in a patient with epilepsy. Epilepsy is characterized by paroxysmal transient disturbances of the electrical activity of the brain that may be manifested as episodic impairment or loss of consciousness, abnormal motor phenomena, psychic or sensory disturbances, or perturbation of the autonomic nervous system.

Cytoplasmic: 1-182
Helical: 183-204
Extracellular: 205-228
Helical: 229-250
Cytoplasmic: 251-261
Helical: 262-279
Extracellular: 280-286
Helical: 287-306
Cytoplasmic: 307-321
Helical: 322-343
Extracellular: 344-357
Helical: 358-377
Extracellular: 378-384
Helical: 385-413
Cytoplasmic: 414-630

Phosphorylation at Ser-438 in response to MAPK activation is increased in stimulated dendrites. Interaction with KCNIP2 and DPP6 propomtes phosphorylation by PKA at Ser-552. Phosphorylation at Ser-552 has no effect on interaction with KCNIP3, but is required for the regulation of channel activity by KCNIP3. Phosphorylation at Ser-552 leads to KCND2 internalization (By similarity).
Phosphorylated by MAPK in response to signaling via the metabotropic glutamate receptor GRM5 (By similarity).
Phosphorylation at Ser-616 is required for the down-regulation of neuronal A-type currents in response to signaling via GRM5 (By similarity).