let's talk about the activation cycle of voltage-gated sodium channels in order to understand the different functional states that a voltage-gated sodium channel can occupy I have to first consider a few important structural features of these channels first of all these channels have four voltage sensor domains only showing two of them here the voltage sensor domains are the locations of the channels voltage sensors the voltage sensors are transmembrane regions of the channels that are enriched and positively charged amino acids within the primary structure the presence of these charges makes them sensitive to the presence of a membrane potential or the electrical field across the membrane next the core of the channel protein is comprised of these pore forming domains the pore forming domains have a couple of important structural features so first of all this is where the location of the selectivity filter is the selectivity filter lines the channel pore and this is what determines ion selectivity for these channels this makes it such that these voltage gated sodium channels are chiefly permeable to sodium ion and not other ions such as potassium calcium and chloride etc another important feature of these domains is this is the location of the voltage gate for the sodium channels the voltage gating mechanism works such that the opening and the closing of the voltage gate is coupled to the position and of the voltage sensors out here in the voltage sensor domains and finally voltage gated sodium channels have an inactivation gate for the channels we're considering this inactivation gate works like a hinged lid that can swing upward and occlude the channel port rendering at non-conductive so voltage-gated sodium channels can exist in three discrete functional States closed open and inactivated in the activation cycle of these channels involves the channel transitioning between these three functional states let's begin with the closed state voltage-gated sodium channels typically exist in the closed state when the membrane potential is relatively negative say somewhere in the neighborhood of the resting membrane potential or a hyperpolarized potential when the membrane potential is relatively negative this creates an electrical field that tends to pull the positively charged voltage sensors downward towards the inner leaf of the plasma membrane this is because of the positive charged residues within the voltage sensors are attracted to the net negativity on the inner leaf of the membrane and repelled from the net positive charge on the outer leaf of the membrane when the voltage sensors are in the downward position this causes the voltage gate to occupy the closed conformation so the voltage gate is shut this blocks the channel pore preventing sodium ions from making their way through the channel pour down sodium's electrochemical gradient which tends to favor outside to inside movement so when the membrane potential depolarizes this makes it less negative on the inner leaf less positive on the outer leaf that allows these positively charged voltage sensors to relax upwards towards the outer leaf of the membrane when this occurs this causes the voltage gate to open the membrane depolarization need not be complete depolarization this can also occur by a partial depolarization somewhere in the range of negative 40 negative 30 millivolts or so can cause the opening of these voltage-gated sodium channels once the voltage gated sodium channels enter this open conformation then sodium ions are able to travel down their electrochemical gradients from outside the cell to inside the cell this produces an inward current of the sodium ions that's ultimately going to be responsible for further membrane depolarization such as during the rising phase of the action potential very soon after the voltage-gated sodium channels enter this open conformation this allows for the inactivation gate to swing shut and a the channel poor thereby rendering the channels non-conductive this state is termed the inactivated state sodium channels enter the inactivated state very quickly after the channels have entered the open state usually somewhere in the range of about a millisecond or so is about the time it takes from the channels to transition between the open state in the inactivated state the inactivation gate acts as a safety mechanism in a way the purpose of it is to prevent a prolonged membrane depolarization while the channel is in the inactivated state the voltage gate itself is still open note the position of the voltage sensors are still in their upward position but again the channel pore is blocked by the presence of that inactivation gate in order to reset the inactivation gate and swing it back out of the way from the channel poor this requires membrane repolarization during membrane repolarization the membrane potential is once again re-established such that we have a negative potential upon the inner leaf of the membrane and a positive potential upon the outer leaf of the membrane this causes the voltage sensors to be pulled back down inward towards the inner leaf of the membrane causing the voltage gate to close and when the voltage gate closes that causes the inactivation gate to swing back away from the channel to its original position once the sodium channel enters the closed state it's ready to participate in the next electrical event involving membrane depolarization that can cause the channel to once again enter the open state those are the three main functional states of the voltage-gated sodium channel the channel typically transitions between these three states unidirectionally going from closed to open to inactivated back to the closed state and if you now understand how this occurs you'll be in a better position to understand how these channels are able to participate in a variety of neurobiological phenomena such as the neuronal action potential