ION CHANNELS IN BIOLOGICAL MEMBRANES AND THE STATE OF THE MIND
Ion channels are made up of protein molecules embedded in cell membranes, which change their conformation in response to physical and chemical stimuli and enter open and shut transitions. This process allows a selective flux of sodium (Na+), potassium (K+), calcium (Ca2+), and chloride (Cl-) ions across the membrane at a rate greater than one million ions per second, which differentiates ion channels from ion transporters. Once activated, depending upon the intended physiological function, the channel activity can exhibit stationary or non-stationary transitions between open and shut states. The channel activity can be terminated by deactivation when the stimulus is removed or enter into a desensitized (for ligand-gated channels) or inactivated state (for voltage-gated channels), a non-conducting state in the presence of the stimulus. These are built-in mechanisms to prevent excessive stimulation or to carry out tasks that require temporal precision. For example, Na+ channel inactivation is critical for the repetitive firing pattern in neurons, and AMPA type glutamate receptor desensitization is critical for fast synaptic transmission leading to spatial and temporal summation.
Broadly, ion channels are classified according to the type of stimulus that activates them; they are ligand-gated (binding of a chemical), voltage-gated (abrupt change in transmembrane voltage), temperature-gated (change in temperature), and mechanical force-gated (sustained or puctate change in the deformation of the plasma membrane). A ligand could be an amino acid (glutamate or glycine), a chemical molecule (acetylcholine, AMPA, or kainate, capsaicin), an ion (H+ or Ca2+), a nucleotide (ATP or GTP), a lipid moiety (arachidonic acid, anandamide), a phosphate group (phosphorylation) or second messengers (PIP2, IP3, cAMP). The ligands can bind to extracellular and intracellular domains of the protein molecule to activate the channel or sensitize the channel to another agonist.
Furthermore, a number of G-protein coupled receptors (GPCRs) are distributed in the plasma membrane. Upon their stimulation, second messengers are produced that can directly activate ion channels or modulate by altering their phosphorylation state. These are classified as metabotropic receptors that can exert an inhibitory or excitatory response on excitable cells. For example, dopamine, serotonin (5-hydroxytryptamine, 5-HT), and norepinephrine (noradrenalin, NE) receptors in the brain are GPCRs and modulate neuronal function profoundly. A decrease in dopamine levels results in Parkinson’s disease; an increase in dopamine levels in certain regions of the brain can bring about craving behaviors and initiate reward pathways; a decrease in serotonin and norepinephrine levels can cause depression and mediate certain modalities of chronic pain conditions. In general, neurochemical levels in the brain modulate ion channel function and alter the excitability of neurons, which defines the state of the mind.
Voltage-gated ion channels exclusively participate in the generation of action potentials, a fundamental binary event that initiates and propagates nerve impulses. Action potentials are initiated at the peripheral nerve terminals when exposed to hot or cold temperatures, but the higher centers of the brain are able to decode these simple binary signals into complex sensory perception. Voltage-gated Na+ channels are responsible for the upstroke of the action potential, causing the depolarization of the membrane and the activation of voltage-gated K+ channels during repolarization of the membrane. Voltage-gated Ca2+ channels are activated during the upstroke of the action potential and the influx of Ca2+ induces Ca2+-induced Ca2+ release from the intracellular stores. Increases in intracellular Ca2+ is responsible for very important functions such as cardiac and skeletal muscle contraction; release of neurotransmitters for synaptic transmission; and long lasting changes in the brain, including memory formation, neuronal plasticity, and neuronal cell death.
The function of ligand-, temperature-, and mechanical force-gated channels is to bring the membrane potential closer to threshold to initiate the action potential generation, or take the membrane potential away from the threshold to prevent the action potential generation. For example, anxiety can be treated effectively by diazepam (Valium), which simply potentiates the inhibitory transmission by augmenting the function of the GABA channel; some of the general anesthetics also act by modulating GABA channels. Activation of GABA channels increases the flux of negatively charged Cl- ions, and hyperpolarizes the membrane making it harder to reach the threshold to generate an action potential. Antidepressants are useful in treating depression by modifying neurochemical levels in the brain to alter excitability. For example, monoamines (dopamine, serotonin, and norepinephrine) play a vital role in modulating neuronal excitability. As indicated earlier dopamine, serotonin (except for 5HT3), and norepinephrine are G-protein coupled metabotropic receptors, activation of which produces second messengers and modulate ligand- and voltage-gated ion channels to bring about desired or undesired effects. Interestingly, these receptors are distributed in specific regions of the brain and control specific emotions and mental state just by altering the excitability of neurons in a given neuronal circuit. The synchronous or asynchronous neuronal activity is propagated to specific region of the brain and this concerted firing pattern from different regions of the brain culminate in a complex integration (as in a symphony orchestra) of these binary signals into an emotional metaphysical realm, which is beyond human comprehension.
Major alterations in a specific neuronal circuit, as a result of change in brain chemistry, is manifested as a mental disease state, which can be recognized and treated. However, subtle changes that cannot be identified by the detection criteria may be at the threshold and can cross in and out of the fine line without conscious realization. In other words, there may be a lot of chatter (noise) below the threshold that can result in tremendous internal turmoil. These neurochemical changes can occur in certain regions of the brain, which control specific emotions. For example, chronic pain conditions known as neuropathic pain that involve higher centers of the brain can not be diagnosed precisely.
The neurochemical changes that occur in an individual can be inherited or acquired during one’s life time. There are several factors that can precipitate such changes, which include medications and nutritional state during pregnancy, hypoxia during birth, breast feeding, closeness with the mother after birth, premature birth, up bringing, stability of a family unit, physical and emotional abuse, socioeconomic status, methods of punishment and reward, physical stature, early childhood friends, what you watch on the television, the value system at home, types of profession the parents are involved in, and plasticity of the brain by the activities during development. These changes are more critical during development because they could lead to long lasting plasticity.
All human beings exhibit aberrations in the brain chemistry; it is the extent that matters, and the spectrum is not restricted. For example, there are individuals who do not believe in the Holocaust and believe that the bringing down of the World Trade Center is a conspiracy. Religious leaders, who are expected to have moral rectitude and high-ground have turned out to be child molesters, pedophiles, and solicitors of homosexual relationships. There are individuals who have a strong conviction that everything happens with the guidance of a higher power and then there are atheists. There are witnesses who have encountered UFOs and strongly believe in their existence. An out of body experience can make one believe that there is life after death. Abortion is considered alright in a group of people and absolutely prohibited in another. There are individuals who are readily willing to take out a precious life for trivial gains.
Religion, which is supposed to provide peace, solace, and hope and enrich the fabric of the society, has been utilized to justify the killing of people with beliefs other than their own. Recent studies suggest that there could be a ‘God gene’ that can result in the way you are molded and this appears to involve the monoamine system in the brain. This means a sect of the population apparently has this gene in them, or it is their upbringing that alters the neurochemistry in such a manner that one becomes essentially gullible to adopt a religious faith; it is the great divide. Complex combinations and permutations of neuronal activity results in a metaphysical state of mind, which is defined as the conscience, which has no color, creed or shape. If you live by your conscience, you will always do the right thing.
Activity-dependent plasticity is critical for neuronal growth; however, connectivity and pruning occurs during development to obtain optimal neuronal integration. As one gets older, the number of neurons decreases; perhaps they are well-connected with impregnated circuits. This might underlie the basis for one’s intelligence (one of the measurable traits). Although, most daily activities (>90%) are mundane and require no great intellectual ability. However, when exposed to a stratum that requires higher brain power, the separation of brain power becomes obvious. A society requires inventors, manufacturers, and consumers. Cloned crops and cattle (invention) can be produced en mass (manufacture) to solve the hunger of the world (consumption). An athlete (inventor) is trained (manufacturer) to entertain millions (consumer). Harnessing the power of the brain can make one achieve the category one chooses to be in, which requires discipline, dedication, passion, hard work, a strong penchant to reach the goal, and an unquenchable desire to contribute to the advancement of the society.
Diseases involving ion channels can arise from the lack or excess of an endogenous ligand or ingestion of an exogenous ligand. Channelopathies are diseases that arise from an inherent defect in the channel function as a result of mutations that have been traced to be familial inheritance or due to random occurrence.