Abstract
The Hv1 channel and voltage-sensitive phosphatases share with voltage-gated sodium, potassium, and calcium channels the ability to detect changes in membrane potential through voltage-sensing domains (VSDs). However, they lack the pore domain typical of these other channels. NaV, KV, and CaV proteins can be found in neurons and muscles, where they play important roles in electrical excitability. In contrast, VSD-containing proteins lacking a pore domain are found in non-excitable cells and are not involved in neuronal signaling. Here, we report the identification of HVRP1, a protein related to the Hv1 channel (from which the name Hv1 Related Protein 1 is derived), which we find to be expressed primarily in the central nervous system, and particularly in the cerebellum. Within the cerebellar tissue, HVRP1 is specifically expressed in granule neurons, as determined by in situ hybridization and immunohistochemistry. Analysis of subcellular distribution via electron microscopy and immunogold labeling reveals that the protein localizes on the post-synaptic side of contacts between glutamatergic mossy fibers and the granule cells. We also find that, despite the similarities in amino acid sequence and structural organization between Hv1 and HVRP1, the two proteins have distinct functional properties. The high conservation of HVRP1 in vertebrates and its cellular and subcellular localizations suggest an important function in the nervous system.
Highlights
The molecular devices responsible for the generation and propagation of electrical signals in excitable tissues are proteins containing voltage-sensing domains (VSDs) [1]
We explored the possibility that the N- or the Cterminus of HVRP1 may be responsible for preventing the opening of the VSD gate in the absence of proper stimulation
All the known VSD-containing proteins involved in neuronal signaling are ion channels containing a pore domain
Summary
The molecular devices responsible for the generation and propagation of electrical signals in excitable tissues are proteins containing voltage-sensing domains (VSDs) [1]. Malfunction of such proteins is the cause of several neurological and cardiovascular diseases, such as epilepsy, episodic ataxia, migraine, periodic paralysis, and cardiac arrhythmia [2]. In most VSD-containing proteins, such as voltage-gated sodium, potassium, and calcium channels, the voltage sensor controls the opening and closing of an ion-conducting pore domain (Fig. 1A). Two classes of proteins have been identified so far, which contain VSDs but do not possess pore domains: voltage-sensitive phosphatases (VSPs) [3] and voltage-gated proton (Hvs) channels [4,5]
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