Hyperpolarization-activated cyclic nucleotide–gated (HCN) channels are integral membrane

proteins Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...

that serve as

nonselective Functional selectivity (or “agonist trafficking”, “biased agonism”, “biased signaling”, "ligand bias" and “differential engagement”) is the ligand-dependent selectivity for certain signal transduction pathways relative to a referen ...

voltage-gated Voltage-gated ion channels are a class of transmembrane proteins that form ion channels that are activated by changes in the electrical membrane potential near the channel. The membrane potential alters the conformation of the channel proteins ...

cation An ion () is an atom or molecule with a net electrical charge. The charge of an electron is considered to be negative by convention and this charge is equal and opposite to the charge of a proton, which is considered to be positive by convent ...

channels Channel, channels, channeling, etc., may refer to: Geography * Channel (geography), in physical geography, a landform consisting of the outline (banks) of the path of a narrow body of water. Australia * Channel Country, region of outback Austral ...

in the

plasma membrane The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment (t ...

s of

heart The heart is a muscular organ in most animals. This organ pumps blood through the blood vessels of the circulatory system. The pumped blood carries oxygen and nutrients to the body, while carrying metabolic waste such as carbon dioxide t ...

and

brain A brain is an organ that serves as the center of the nervous system in all vertebrate and most invertebrate animals. It is located in the head, usually close to the sensory organs for senses such as vision. It is the most complex organ in a v ...

cells. HCN channels are sometimes referred to as pacemaker channels because they help to generate rhythmic activity within groups of heart and brain cells. HCN channels are activated by membrane hyperpolarization, are permeable to and , and are constitutively open at voltages near the resting membrane potential. HCN channels are encoded by four

gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...

s ( HCN1, 2, 3, 4) and are widely expressed throughout the heart and the

central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all par ...

. The

current Currents, Current or The Current may refer to: Science and technology * Current (fluid), the flow of a liquid or a gas ** Air current, a flow of air ** Ocean current, a current in the ocean *** Rip current, a kind of water current ** Current (stre ...

through HCN channels, designated ''I''_f or ''I''_h, plays a key role in the control of cardiac and neuronal rhythmicity and is called the

pacemaker current The pacemaker current (or I''f'', or IK''f'', also referred to as the funny current) is an electric current in the heart that flows through the HCN channel or pacemaker channel. Such channels are important parts of the electrical conduction system ...

or "funny" current. Expression of single

isoform A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene or gene family and are the result of genetic differences. While many perform the same or similar biological roles, some isof ...

s in heterologous systems such as human embryonic kidney ( HEK) cells, Chinese hamster ovary (

CHO Cho or CHO may refer to: People * Chief Happiness Officer Surnames * Cho (Korean surname), one romanization of the common Korean surname * Zhuo (), romanized Cho in Wade–Giles, Chinese surname * Cho, a Minnan romanization of the Chinese sur ...

) cells and ''

Xenopus ''Xenopus'' () (Gk., ξενος, ''xenos''=strange, πους, ''pous''=foot, commonly known as the clawed frog) is a genus of highly aquatic frogs native to sub-Saharan Africa. Twenty species are currently described within it. The two best-known ...

oocytes An oocyte (, ), oöcyte, or ovocyte is a female gametocyte or germ cell involved in reproduction. In other words, it is an immature ovum, or egg cell. An oocyte is produced in a female fetus in the ovary during female gametogenesis. The female ge ...

yield homotetrameric channels able to generate ion currents with properties similar to those of the native ''I''_f/''I''_h current, but with quantitative differences in the voltage-dependence, activation/deactivation kinetics and sensitivity to the nucleotide

cyclic AMP Cyclic adenosine monophosphate (cAMP, cyclic AMP, or 3',5'-cyclic adenosine monophosphate) is a second messenger important in many biological processes. cAMP is a derivative of adenosine triphosphate (ATP) and used for intracellular signal transd ...

(cAMP): HCN1 channels have a more positive threshold for activation, faster activation kinetics, and a lower sensitivity to cAMP, while

HCN4 Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 4 is a protein that in humans is encoded by the ''HCN4'' gene. There are four HCN channels. HCN4 is prominently expressed in the pace maker region of the mammalian hear ...

channels are slowly gating and strongly sensitive to cAMP. HCN2 and HCN3 have intermediate properties.

Structure

Hyperpolarization-activated and cyclic nucleotide–gated (HCN) channels belong to the superfamily of voltage-gated K⁺ (Kv) and cyclic nucleotide–gated (CNG) channels. HCN channels are thought to consist of four either identical or non-identical subunits that are integrally embedded in the

cell membrane The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment ( ...

to create an ion-conducting pore. Each subunit comprises six membrane-spanning (S1–6) domains which include a putative voltage sensor (S4) and a pore region between S5 and S6 carrying the GYG triplet signature of K⁺-permeable channels, and a

cyclic nucleotide-binding domain Proteins that bind cyclic nucleotides (cAMP or cGMP) share a structural domain of about 120 residues. The best studied of these proteins is the prokaryotic catabolite gene activator (also known as the cAMP receptor protein) (gene crp) where such ...

(CNBD) in the C-terminus. HCN isoforms are highly conserved in their core transmembrane regions and cyclic nucleotide binding domain (80–90% identical), but diverge in their amino- and carboxy-terminal cytoplasmic regions. HCN channels are regulated by both intracellular and extracellular molecules, but most importantly, by cyclic nucleotides (cAMP, cGMP, cCMP). Binding of cyclic nucleotides lowers the threshold potential of HCN channels, thus activating them. cAMP is a primary agonist of HCN2 while cGMP and cCMP may also bind to it. All three, however, are potent agonists.

Cardiac function

HCN4 is the main isoform expressed in the

sinoatrial node The sinoatrial node (also known as the sinuatrial node, SA node or sinus node) is an oval shaped region of special cardiac muscle in the upper back wall of the right atrium made up of cells known as pacemaker cells. The sinus node is approximat ...

, but low levels of HCN1 and HCN2 have also been reported. The current through HCN channels, called the

(''I''_f), plays a key role in the generation and modulation of

cardiac rhythmicity Cardiac rhythmicity is the spontaneous depolarization and repolarization event that occurs in a repetitive and stable manner within the cardiac muscle. Rhythmicity is often abnormal or lost in cases of cardiac dysfunction or cardiac failure. It is t ...

, as they are responsible for the spontaneous depolarization in pacemaker action potentials in the heart. HCN4 isoforms are regulated by cCMP and cAMP and these molecules are agonists at ''I''_f.

Function in the nervous system

All four HCN subunits are expressed in the brain. In addition to their proposed roles in pacemaking rhythmic or oscillatory activity, HCN channels may control the way that

neuron A neuron, neurone, or nerve cell is an electrically excitable cell that communicates with other cells via specialized connections called synapses. The neuron is the main component of nervous tissue in all animals except sponges and placozoa. N ...

s respond to synaptic input. Initial studies suggest roles for HCN channels in sour taste, coordinated motor behavior and aspects of learning and memory. Clinically, there is evidence that HCN channels play roles in

epilepsy Epilepsy is a group of non-communicable neurological disorders characterized by recurrent epileptic seizures. Epileptic seizures can vary from brief and nearly undetectable periods to long periods of vigorous shaking due to abnormal electrical ...

and

neuropathic pain Neuropathic pain is pain caused by damage or disease affecting the somatosensory system. Neuropathic pain may be associated with abnormal sensations called dysesthesia or pain from normally non-painful stimuli (allodynia). It may have continuous ...

. HCN channels have been shown to be important for activity-dependent mechanisms for olfactory sensory neuron growth. HCN1 and 2 channels have been found in

dorsal root ganglia A dorsal root ganglion (or spinal ganglion; also known as a posterior root ganglion) is a cluster of neurons (a ganglion) in a dorsal root of a spinal nerve. The cell bodies of sensory neurons known as first-order neurons are located in the do ...

basal ganglia The basal ganglia (BG), or basal nuclei, are a group of subcortical nuclei, of varied origin, in the brains of vertebrates. In humans, and some primates, there are some differences, mainly in the division of the globus pallidus into an extern ...

, and the

dendrite Dendrites (from Greek δένδρον ''déndron'', "tree"), also dendrons, are branched protoplasmic extensions of a nerve cell that propagate the electrochemical stimulation received from other neural cells to the cell body, or soma, of the n ...

s of neurons in the

hippocampus The hippocampus (via Latin from Greek , 'seahorse') is a major component of the brain of humans and other vertebrates. Humans and other mammals have two hippocampi, one in each side of the brain. The hippocampus is part of the limbic system, a ...

. It has been found that human cortical neurons have particularly high amount of HCN1 channel expression in all layers. HCN channel trafficking along dendrites in the hippocampus of rats has shown that HCN channels are quickly shuttled to the surface in response to neural activity. HCN channels have also been observed in the retrotrapezoid nucleus (RTN), a respiratory control center that responds to chemical signals such as CO₂. When HCN is inhibited,

serotonin Serotonin () or 5-hydroxytryptamine (5-HT) is a monoamine neurotransmitter. Its biological function is complex and multifaceted, modulating mood, cognition, reward, learning, memory, and numerous physiological processes such as vomiting and vas ...

fails to stimulate chemoreceptors in the RTN. This illustrates a connection between HCN channels and respiratory regulation. Due to the complex nature of HCN channel regulation, as well as the complex interactions between multiple ion channels, HCN channels are fine-tuned to respond to certain thresholds and agonists. This complexity is believed to affect

neural plasticity Neuroplasticity, also known as neural plasticity, or brain plasticity, is the ability of neural networks in the brain to change through growth and reorganization. It is when the brain is rewired to function in some way that differs from how it ...

History

HCN channel was first identified in 1976 in the heart by Noma and Irisawa and characterized by Brown, Difrancesco and Weiss

References

External links