Our promise to you:
Guaranteed product quality, expert customer support.
Kcnc3 is also named Kv3.3. The Kv3.3 voltage-dependent K+ channel belongs to a class of ion channels sometimes termed ‘high-threshold’ or ‘high voltage-activated’ channels. These are typical delayed rectifier channels that are activated only when the potential is greater than ~ 20mv. Therefore, they contribute very little to resting potassium conductance, but are activated during the rise of action potential. Kv3.3 channels also activate and deactivate response voltage changes very quickly. Therefore, these channels produce very fast repolarization of the action potential with little or no relative refractory period, enabling neurons that express these channels to excite the action potential sequence at high frequencies. In the case of maintaining depolarization, the Kv3.3 channel experienced slow and partial deactivation, with a time course of several hundred milliseconds. This inactivation occurs through the n-type inactivation mechanism, which is eliminated by the loss of cytoplasm at the n-end of the pathway. Inactivation can also be regulated by activating protein kinase C. There is evidence that the phosphorylation of two serine residues in the n terminal region of Kv3.3 can prevent inactivation in the N-terminal region.
Kv3.3 channels are expressed in neurons that fire at high rates, particularly in the cerebellum and brainstem. High levels are also found in inhibitory parvalbumin-containing cortical interneurons that typically are capable of firing at hundreds of hertz, as well as in GABA-ergic interneurons in other parts of the nervous system. Many such neurons also express the Kv3.1 channel, and the high voltage-activated channels in such neurons may be heteromeric channels containing both Kv3.3 and Kv3.1. The Kv3.3 is also strongly expressed in most auditory brainstem nuclei, where neurons may be fired at a frequency of up to 600-800 Hertz to process auditory information.
Kv3.3 and SCA13
Spinalcerebellar ataxia type 13 (SCA13) is an autosomal dominant inherited neurodegenerative disease characterized by cerebellar atrophy, especially the vermis, leading to a cerebellar syndrome with dysarthria and nystagmus. It is sometimes accompanied by pyramidal signs, epilepsy, auditory deficits, and mild intellectual disability. The disease is caused by missense mutations in the KCNC3 gene.
One study demonstrating a link between human mutations in KCNC3 and ataxia reporting two different channel mutations: R420H, which leads to adult onset ataxia, and F448L, which results in childhood onset ataxia with cognitive delay. The R420H mutation is located in the S4 transmembrane domain that represents the major voltage sensor in these channels (Figure 1). Another mutation (R423H) has also been found in the S4 domain, but, in contrast to R420H, this produces a severe early onset spinocerebellar ataxia. The early onset F448L mutation is located in the S5 transmembrane region of the protein, close to the pore of the channel (Figure 1).
Figure 1 The Kv3.3 channel
While the primary focus of the effects of Kv3.3 mutations has been on cerebellar function, it is evident that other neuronal circuits can be severely impacted. A clear example of this is found in the auditory system where Kv3.3 channels are found at high levels in brain-stem circuits underlying sound localization. Moreover, when co-expressed with wild type Kv3.3 channels, with which they would be expected to form hetero-tetramers, R420H and R423H have a dominant-negative effect, suppressing overall current amplitude. In contrast to loss-of-function mutations such as R420H and R423H, other disease-causing mutations, such as the early onset F448L mutation, result in fully functional Kv3.3 channels that make it to the plasma membrane.
The Kv3.3 channel in most SCA13 patients is likely to be a tetramer containing both wild type and mutant channels. One report showed that co-expressed the late onset R420H mutant with wild type Kv3.3 channels. Although R420H reduced overall current amplitude, the kinetic behavior of the heteromeric channels was identical to that of homomeric wild type Kv3.3 channels. In contrast, the voltage dependence of the current that results from heteromeric R423H/wild type channels was found to be shifted to negative potentials. In this respect, the R423H/wild type heteromeric channels resemble F448L mutant channels, which also cause the early onset disease. Moreover, in addition to the altered voltage dependence, the kinetic behavior of the R423H/wild type heteromers was also different from that of wild type Kv3.3 homomers.
Lessons from Kv3.3 knockout animals
Kv3.3 channels are expressed in both the somata and the dendrites of cerebellar Purkinje cells. Consistent with a role for Kv3.3 in shaping the firing patterns of these neurons, Purkinje cell action potentials are broader in Kv3.3−/− mice than in wild type animals .These electro-physiological changes can be rescued by re-introducing wild type Kv3.3 channels selectively into Purkinje cells of Kv3.3−/− animals, but this does not rescue the motor behaviors. The excitability of the distal dendrites, and the amplitude of cytoplasmic Ca2+ signals evoked by stimulation of the dendrites, is also increased in Purkinje cells of Kv3.3−/− knockout mice. A much more severe motor phenotype is observed when the Kv3.3 gene is deleted in combination with that for the closely related channel Kv3.1. Such double knockout animals have severe ataxia as well as other disorders of movement. They are constitutively hyperactive, appear unbalanced when moving, and undergo whole-body jerks every few seconds.