HCN channel
Encyclopedia
Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are proteins that serve as ion channel
s across the plasma membrane of heart and brain 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 encoded by four genes (HCN1-4) and are widely expressed throughout the heart and the central nervous system.
The current flowing through HCN channels, designated If or Ih, plays a key role in the control of cardiac and neuronal rhythmicity ("pacemaker current"). Expression of single isoforms in heterologous systems (human embryonic kidney -HEK- cells, Chinese hamster ovary -CHO- cells, and Xenopus oocytes) yields homotetrameric channels able to generate ion currents with properties similar to those of the native If/Ih current, but with quantitative differences in the voltage-dependence, activation/deactivation kinetics and sensitivity to the nucleotide cyclic AMP
(cAMP): HCN1
channels show the more positive threshold for activation, the fastest activation kinetics, and the lowest sensitivity to cAMP, while HCN4
channels are slowly gating and strongly sensitive to cAMP. HCN2
and HCN3
have intermediate properties.
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 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 (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. The ribbon model to the right depicts HCN1.
The current flowing through HCN channels, called the funny current
or pacemaker current (If), plays a key role in the generation and modulation of cardiac rhythmicity
.
Stimulation of a certain receptor in the prefrontal cortex known as the alpha2A-adrenoceptor (also known as the alpha-2A adrenergic receptor
) has been shown to improve working memory
, or the brain’s capacity to retain, manipulate and utilize information relevant to one’s surroundings. This function of the brain is critical to normal cognitive performance in everyday life. Working memory impairment can dramatically affect cognitive function, and it is a symptom of many neurological diseases, including schizophrenia
. Thus the alpha2A-adrenoceptor is the target of current research seeking to prevent or counteract working memory impairment. The Arnsten Lab at Yale University recently found that HCN channels serve as the intracellular mechanism through which stimulation of alpha2A-adrenoceptors improves working memory. [results reviewed in Robbins & Arnsten 2009]
The lab found that directly closing HCN channels with the drug ZD7288 strengthened working memory on the cellular level in much the same manner as stimulation of alpha2A-adrenoceptors themselves. By directly inhibiting HCN channels in vitro, either with the drug ZD7288 or viral knockdown of HCN1
expression, the Arnsten lab was able to improve working memory in rats. Interestingly, both alpha2A-adrenoceptors and HCN channels were observed to be co-localized on small projections of neuron membrane known as dendritic spine
s. These findings suggest that dendritic spine
s are the structures within which HCN channels and alpha2A-adrenoceptors interact to affect working memory.
The Arnsten Lab hypothesized a role for HCN channels in working memory impairment. If, because of neurological disease, HCN channels in dendritic spines are over-active, they would prevent electrical impulses from traveling through the spine. Too many open HCN channels would increase the conductivity of the membrane to such an extent than many impulses entering the neuron through the spine would effectively be shunted out of the cell. This would prevent information from being reliably passed between the networks of neurons that form the cellular basis of working memory, causing working memory impairment. Therefore, drugs that are capable of closing HCN channels would strengthen the connectivity of the networks of neurons necessary of working memory, and ameliorate the working memory impairment observed in diseases like schizophrenia. On a side note, ZD7288 is not being considered as a possible drug candidate because it is unable to cross the blood-brain barrier, and thus cannot be administered systemically. However, other drugs such as the alpha2A-adrenoceptor agonist guanfacine
are capable of indirectly closing HCN channels, and could prove to be useful treatments for working memory impairment.
Ion channel
Ion channels are pore-forming proteins that help establish and control the small voltage gradient across the plasma membrane of cells by allowing the flow of ions down their electrochemical gradient. They are present in the membranes that surround all biological cells...
s across the plasma membrane of heart and brain 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 encoded by four genes (HCN1-4) and are widely expressed throughout the heart and the central nervous system.
The current flowing through HCN channels, designated If or Ih, plays a key role in the control of cardiac and neuronal rhythmicity ("pacemaker current"). Expression of single isoforms in heterologous systems (human embryonic kidney -HEK- cells, Chinese hamster ovary -CHO- cells, and Xenopus oocytes) yields homotetrameric channels able to generate ion currents with properties similar to those of the native If/Ih current, but with quantitative differences in the voltage-dependence, activation/deactivation kinetics and sensitivity to the nucleotide cyclic AMP
Cyclic adenosine monophosphate
Cyclic adenosine monophosphate is a second messenger important in many biological processes...
(cAMP): HCN1
HCN1
Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 1 is a protein that in humans is encoded by the HCN1 gene.- External links :...
channels show the more positive threshold for activation, the fastest activation kinetics, and the lowest sensitivity to cAMP, while HCN4
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 heart. Some humans with bradycardia and Sick sinus syndrome...
channels are slowly gating and strongly sensitive to cAMP. HCN2
HCN2
Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated ion channel 2 is a protein that in humans is encoded by the HCN2 gene.-Interactions:HCN2 has been shown to interact with HCN1 and HCN4.-Function:...
and HCN3
HCN3
Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 3 is a protein that in humans is encoded by the HCN3 gene....
have intermediate properties.
Structure
Potassium channel
In the field of cell biology, potassium channels are the most widely distributed type of ion channel and are found in virtually all living organisms. They form potassium-selective pores that span cell membranes...
(Kv) and cyclic nucleotide-gated
Cyclic nucleotide-gated ion channel
Cyclic nucleotide-gated ion channels are ion channels that function in response to the binding of cyclic nucleotides. CNG channels are nonselective cation channels that are found in the membranes of various types of cells.- Discovery :...
(CNG) channels. HCN channels are thought to consist of four either identical or non-identical subunits that are integrally embedded in the cell membrane 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 (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. The ribbon model to the right depicts HCN1.
Function in the Heart
HCN4 is the main isoform expressed in the sinoatrial node, but low levels of HCN1 and HCN2 have also been reported.The current flowing through HCN channels, called the funny current
Funny current
Funny current refers to a specific current in the heart....
or pacemaker current (If), plays a key role in the generation and modulation of cardiac rhythmicity
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....
.
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 also control the way that neurons 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 and neuropathic painCurrent Brain-related Research
HCN Channels and the Prefrontal CortexStimulation of a certain receptor in the prefrontal cortex known as the alpha2A-adrenoceptor (also known as the alpha-2A adrenergic receptor
Alpha-2A adrenergic receptor
The alpha-2A adrenergic receptor , also known as ADRA2A, is an alpha-2 adrenergic receptor, and also denotes the human gene encoding it.-Role in Central Nervous System:...
) has been shown to improve working memory
Working memory
Working memory has been defined as the system which actively holds information in the mind to do verbal and nonverbal tasks such as reasoning and comprehension, and to make it available for further information processing...
, or the brain’s capacity to retain, manipulate and utilize information relevant to one’s surroundings. This function of the brain is critical to normal cognitive performance in everyday life. Working memory impairment can dramatically affect cognitive function, and it is a symptom of many neurological diseases, including schizophrenia
Schizophrenia
Schizophrenia is a mental disorder characterized by a disintegration of thought processes and of emotional responsiveness. It most commonly manifests itself as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and it is accompanied by significant social...
. Thus the alpha2A-adrenoceptor is the target of current research seeking to prevent or counteract working memory impairment. The Arnsten Lab at Yale University recently found that HCN channels serve as the intracellular mechanism through which stimulation of alpha2A-adrenoceptors improves working memory. [results reviewed in Robbins & Arnsten 2009]
The lab found that directly closing HCN channels with the drug ZD7288 strengthened working memory on the cellular level in much the same manner as stimulation of alpha2A-adrenoceptors themselves. By directly inhibiting HCN channels in vitro, either with the drug ZD7288 or viral knockdown of HCN1
HCN1
Potassium/sodium hyperpolarization-activated cyclic nucleotide-gated channel 1 is a protein that in humans is encoded by the HCN1 gene.- External links :...
expression, the Arnsten lab was able to improve working memory in rats. Interestingly, both alpha2A-adrenoceptors and HCN channels were observed to be co-localized on small projections of neuron membrane known as dendritic spine
Dendritic spine
A dendritic spine is a small membranous protrusion from a neuron's dendrite that typically receives input from a single synapse of an axon. Dendritic spines serve as a storage site for synaptic strength and help transmit electrical signals to the neuron's cell body...
s. These findings suggest that dendritic spine
Dendritic spine
A dendritic spine is a small membranous protrusion from a neuron's dendrite that typically receives input from a single synapse of an axon. Dendritic spines serve as a storage site for synaptic strength and help transmit electrical signals to the neuron's cell body...
s are the structures within which HCN channels and alpha2A-adrenoceptors interact to affect working memory.
The Arnsten Lab hypothesized a role for HCN channels in working memory impairment. If, because of neurological disease, HCN channels in dendritic spines are over-active, they would prevent electrical impulses from traveling through the spine. Too many open HCN channels would increase the conductivity of the membrane to such an extent than many impulses entering the neuron through the spine would effectively be shunted out of the cell. This would prevent information from being reliably passed between the networks of neurons that form the cellular basis of working memory, causing working memory impairment. Therefore, drugs that are capable of closing HCN channels would strengthen the connectivity of the networks of neurons necessary of working memory, and ameliorate the working memory impairment observed in diseases like schizophrenia. On a side note, ZD7288 is not being considered as a possible drug candidate because it is unable to cross the blood-brain barrier, and thus cannot be administered systemically. However, other drugs such as the alpha2A-adrenoceptor agonist guanfacine
Guanfacine
Guanfacine is a sympatholytic. It is an agonist of the α2A subtype of norepinephrine receptors. These receptors are concentrated heavily in the prefrontal cortex and the locus coeruleus, with the potential to improve attention abilities via modulating post-synaptic α2A receptors in the prefrontal...
are capable of indirectly closing HCN channels, and could prove to be useful treatments for working memory impairment.