HCN3

HCN3, encoded by the gene hcn3, is a hyperpolarization-activated cyclic nucleotide-gated potassium channel. HCN3 is widely expressed at low levels throughout both the CNS and PNS. It is involved in the generation of the I(h) current which controls neuron excitability.

hcn3 is the coding gene for HCN3. In humans, hcn3 is located on chromosome 1q22 and is made up of 8 exons, all of which are coding.

A splice variant of HCN3 has been identified in the liver and kidney, although the functional importance of this transcript remains to be established. [2340]

The human HCN3 protein is composed of 774 amino acids (aa) and has a molecular weight of 86 Kda.

To date, no PTMs, specific to HCN3, have been studied.

Visual Representation of HCN3 Structure
Methodology for visual representation of structure available here

Human HCN3 is the smallest member within the human HCN protein family, primarily due to distinct variations in the lengths of its N- and C-terminal domains. Specifically, the N-terminal domain of hHCN3 consists of 88 amino acids, while the C-terminal domain comprises 220 amino acids. In contrast, the corresponding domains in hHCN4 extend to 257 and 481 amino acids, respectively. As a consequence of these variations, HCN3 shares an overall sequence homology of approximately 46-56% with other hHCNs. Nevertheless, the core region of HCN3, encompassing the six transmembrane segments, the pore region, the C-linker, and the cyclic nucleotide-binding domain (CNBD), exhibits a high degree of conservation across all hHCNs. [56].

HCN3 exhibits relatively slow activation kinetics, characterized by time constants spanning from 250 to 400 milliseconds at a membrane potential of -140 mV. These activation kinetics are comparatively slower than those of HCN1 and HCN2 but faster than the corresponding kinetics of HCN4. The midpoint of activation (V1/2) for HCN3 falls within the range of -80 to -95 mV, and its reversal potential (Erev) has been determined to be approximately -20.5 +/- 4 mV. Consequently, HCN3 demonstrates a permeability ratio (PNa/Pk) of 0.3. [56] [457]

Single channel unitary conductance

There has been no single channel unitary conductance recordings for HCN3.

Model

Cellular and tissue

In the CNS, HCN3 is expressed at very low levels throughout the brain, with a few expression hotspots that appear to vary across species [338]. In humans, these hotspots were identified as the cerebellum, the olfactory bulb, and some hypothalamic nuclei [337] [2306] [457].

In the PNS, HCN3 has been identified in 60% of small (<20 μm diameter) and medium–large (>20 μm diameter) neuron subtypes. In the DRG neurons, HCN3 was found expressed in about 35% of small unmyelinated neurons, 86% of large myelinated neurons, and 63% of small and medium neurons with nociceptive function [2342]. HCN3 was also detected in heart muscles, albeit at relatively low levels [457].

For a more detailed map immunohistochemical localisation of HCN3, please consult the following paper [323]

Developmental

The highest expression level of HCN3 was found to be in the fetal brain. This notable finding was universal across most species, pointing to a potential role of HCN3 in early brain development. [56] [2306]

To date, the subcellular location of HCN3 has not been identified in the CNS.

HCN3 is responsible for generating the I(h) current in the tissues where it is present. In particular, studies have demonstrated that HCN3 plays a pivotal role in maintaining excitability and promoting rhythmic burst firing within hypothalamic nuclei. [2341]

Given its location in nociceptive neurons, HCN3 is thought to contribute to their intrinsic excitability. HCN3 deletion experiments have revealed varying effects: small neuron firing was minimally affected, while the firing of medium-sized neurons was enhanced. However, it is worth noting that HCN3 knockout mice primarily exhibited increased mechanical hyperalgesia, with levels of mechanical allodynia and thermal hyperalgesia remaining comparable to those in wild-type mice. Despite its presence in PNS neurons and its role in modulating their excitability, HCN3 does not appear to play a prominent role in the processing of acute, neuropathic, or inflammatory pain. [2342] [2318]

Cardiomyocytes of HCN3-deficient mice exhibited a notable reduction of approximately 30% in the total I(h) current. Interestingly, these mice lacking HCN3 did not manifest any pathological phenotypes and remained viable and in good health. These results suggest that while HCN3 may not be indispensable, it is likely to exert a significant influence on the configuration of the cardiac action potential waveform. [2342] [2343]

HCN3 is thought to also contribute to the coordination of proximal-to-distal peristalsis of the upper urinary tract. [2344]

Channelopathies

Single gene diseases associated with HCN3 have not been yet identified. However, HCN3 expression has been found upregulated in certain neuroblastoma tissue. Mutations in HCN3 were also identified in certain cases of epilepsy [2319].

cAMP & cGMP

Despite having a cAMP-binding domain, HCN3 is largely insensitive to both cAMP and cGMP [2318]. cAMP and cGMP have no significant impact on activation kinetics but do induce a 5 mV shift of the half-maximal activation voltage (V1/2) to more hyperpolarized potentials [55]. This lack of sensitivity of HCN3, despite harboring a functional CNBD, has been explained by its shorter C-terminal sequence, which alters the normal autoinhibition of the channel [2293].

PIP(2)
As with all HCNs, intracellular phosphatidylinositol-4,5-bisphosphate (PIP(2)) shifts HCN3 activation to more depolarized potentials and accelerated activation kinetics [2341].

For further compounds interactions, please consult the following resource

Contributors: Katherine Johnston, Rajnish Ranjan, Michael Schartner, Nitin Khanna