Tertiapin is a 21-amino acid peptide isolated from venom of the

European honey bee The western honey bee or European honey bee (''Apis mellifera'') is the most common of the 7–12 species of honey bees worldwide. The genus name ''Apis'' is Latin for 'bee', and ''mellifera'' is the Latin for 'honey-bearing' or 'honey-carrying', ...

(''Apis mellifera''). It blocks two different types of potassium channels, inward rectifier potassium channels (Kir) and calcium activated large conductance potassium channels (BK). PDB 1ter EBI

Sources

Tertiapin is a peptidic component of the

venom Venom or zootoxin is a type of toxin produced by an animal that is actively delivered through a wound by means of a bite, sting, or similar action. The toxin is delivered through a specially evolved ''venom apparatus'', such as fangs or a sti ...

of the

(''Apis mellifera'').

Chemistry

Tertiapin peptide is composed of 21 amino acids with the sequence: Ala-Leu-Cys-Asn-Cys-Asn-Arg-Ile-Ile-Ile-Pro-His-Met-Cys-Trp-Lys-Lys-Cys-Gly-Lys-Lys.
The methionine residue is sensitive to oxidation, reducing the ability to block the ionic channels. Methionine can be substituted by glutamine in order to prevent the oxidation. The new synthesized peptide is named Tertiapin-Q and does not show any functional change as compared to the original peptide, which makes it a more suitable research tool.

Target and mode of action

Tertiapin has been described as a potent

potassium channel blocker Potassium channel blockers are agents which interfere with conduction through potassium channels. Medical uses Arrhythmia Potassium channel blockers used in the treatment of cardiac arrhythmia are classified as class III antiarrhythmic age ...

, acting on two different types of K+ channels.

Inward rectifier potassium channels

Tertiapin binds specifically to different subunits of the inward rectifier potassium channel (Kir), namely GIRK1 (Kir 3.1),

GIRK4 G protein-activated inward rectifier potassium channel 4 (GIRK-4) is a protein that in humans is encoded by the ''KCNJ5'' gene and is a type of G protein-gated ion channel. Function Potassium channels are present in most mammalian cells, wher ...

(Kir 3.4) and ROMK1 (Kir 1.1), inducing a dose-dependent block of the potassium current. It is thought that tertiapin binds to the Kir channel with its α-helix situated at the C-terminal of the peptide. This α-helix is plugged into the external end of the conduction pore, thereby blocking the channel. The N-terminal of the peptide sticks out of the extracellular side. Tertiapin has a high affinity for Kir channels with approximately Kd = 8 nM for GIRK1/4 channels and Kd = 2 nM for ROMK1 channels.
In contrast to the voltage-gated K+ channels, Kir channels are more permeable to K⁺ during hyperpolarization than during depolarization. A voltage-dependent blockade by intracellular cations at voltages more positive than the K⁺ reversal potential is the mechanism underlying this feature. At more negative voltages the Kir channels are responsible for an inward K+ current. Therefore K_ir channels contribute to the maintenance of the

resting potential The relatively static membrane potential of quiescent cells is called the resting membrane potential (or resting voltage), as opposed to the specific dynamic electrochemical phenomena called action potential and graded membrane potential. The re ...

, the duration of the action potential and the neuronal excitability.
GIRK1 and -4 are subunits of the muscarinic potassium channels (KACh) and have an important role in the slowing down of the heart rate in response to parasympathetic stimulation via

acetylcholine Acetylcholine (ACh) is an organic compound that functions in the brain and body of many types of animals (including humans) as a neurotransmitter. Its name is derived from its chemical structure: it is an ester of acetic acid and choline. Par ...

. KAch channels activate during hyperpolarization, prolonging the

cardiac action potential Unlike the action potential in skeletal muscle cells, the cardiac action potential is not initiated by nervous activity. Instead, it arises from a group of specialized cells known as pacemaker cells, that have automatic action potential generati ...

by inflow of potassium ions and reducing the frequency of action potential generation. An inhibition by tertiapin will result in a shorter cardiac action potential with loss of parasympathetic control, resulting in a faster heart rate
ROMK is found in the kidneys where it contributes to K⁺ recycling. An inhibition will result in loss of potassium, as observed in

Bartter syndrome Bartter syndrome (BS) is a rare inherited disease characterised by a defect in the thick ascending limb of the loop of Henle, which results in low potassium levels (hypokalemia), increased blood pH (alkalosis), and normal to low blood pressure. T ...

, which can be caused by mutations in the ROMK channels.

BK channels

The second type of potassium channel that tertiapin blocks is the calcium activated large conductance potassium channel (BK). The block of BK cells is voltage-, concentration- and use-dependent, meaning the blockage changes with different stimulation voltages and frequencies, different concentrations and with the duration of application of tertiapin. The

IC50 Half maximal inhibitory concentration (IC50) is a measure of the potency of a substance in inhibiting a specific biological or biochemical function. IC50 is a quantitative measure that indicates how much of a particular inhibitory substance (e. ...

for BK channels is 5.8 nM.
The BK channels have a role in the onset of the

afterhyperpolarization Afterhyperpolarization, or AHP, is the hyperpolarizing phase of a neuron's action potential where the cell's membrane potential falls below the normal resting potential. This is also commonly referred to as an action potential's undershoot phas ...

, thereby shortening the action potential and enhancing the speed of repolarization. Total blockage by tertiapin prolongs the duration of the action potential and inhibits the afterhyperpolarization amplitude, leading to an increase of the neuronal excitability.
Tertiapin inhibits the BK channels only after a minimal stimulation of 15 minutes, in contrast with less than a minute for the GIRK channels. For this reason it is thought that the mode of action of tertiapin is different for each channel type.

Toxicity

Tertiapin is a compound of the honey bee venom (

apitoxin Apitoxin or bee venom is the venom produced by the honey bee. It is a cytotoxic and hemotoxic bitter colorless liquid containing proteins, which may produce local inflammation. It may have similarities to sea nettle toxin. Components Bee venom ...

) that causes pain and signs of inflammation around the sting, but a great number of stings can be lethal (

LD50 In toxicology, the median lethal dose, LD50 (abbreviation for "lethal dose, 50%"), LC50 (lethal concentration, 50%) or LCt50 is a toxic unit that measures the lethal dose of a given substance. The value of LD50 for a substance is the dose requ ...

is 18-22 stings per kg for humans). An

anaphylactic shock Anaphylaxis (Greek: 'up' + 'guarding') is a serious, potentially fatal allergic reaction and medical emergency that is rapid in onset and requires immediate medical attention regardless of the use of emergency medication on site. It typically ...

can develop if a person has an allergy to the venom. In that case even one sting can be lethal.

Therapeutic use

As a paradox to the symptoms after a bee sting, bee venom is used for treatment of pain, inflammation (e.g.

rheumatoid arthritis Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects synovial joint, joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and h ...

) and

multiple sclerosis Multiple sclerosis (MS) is an autoimmune disease resulting in damage to myelinthe insulating covers of nerve cellsin the brain and spinal cord. As a demyelinating disease, MS disrupts the nervous system's ability to Action potential, transmit ...

. Tertiapin may contribute to this effect by prolonging the depolarization phase by blocking the BK channels. Eventually this will lead to inactivation of the voltage-gated Na+ channels of the dorsal root ganglion neurons, reducing sensory transmission to the central nervous system.
Excessive stimulation with acetylcholine can induce an AV-block in the heart as shown in guinea pigs, which can be prevented by blockage of the KAch channels by tertiapin. This suggests a possible therapeutic role in excessive parasympathetic innervation or inferior

myocardial infarction A myocardial infarction (MI), commonly known as a heart attack, occurs when Ischemia, blood flow decreases or stops in one of the coronary arteries of the heart, causing infarction (tissue death) to the heart muscle. The most common symptom ...

References

{{Reflist Ion channel toxins Neurotoxins