Differential Distribution and Function of Hyperpolarization-Activated Channels in Sensory Neurons and Mechanosensitive Fibers

Abstract

Sensory neurons express hyperpolarization-activated currents (I H ) that differ in magnitude and kinetics within the populations. We investigated the structural basis for these differences and explored the functional role of the I H channels in sensory neurons isolated from rat nodose ganglia. Immunohistochemical studies demonstrated a differential distribution of hyperpolarization-activated cyclic nucleotide-gated (HCN) protein (HCN1, HCN2, HCN4) in sensory neurons and peripheral terminals. HCN2 and HCN4 immunoreactivity was present in all nodose neurons. In contrast, only 20% of the total population expressed HCN1 immunoreactivity. HCN1 did not colocalize with IB4 (a marker for C-type neurons), and only 15% of HCN1-positive neurons colocalized with immunoreactivity for the vanilloid receptor VR1, another protein associated primarily with C-type neurons. Therefore, most HCN1-containing neurons were A-type neurons. In further support, HCN1 was present in the mechanosensitive terminals of myelinated but not unmyelinated sensory fibers, whereas HCN2 and HCN4 were present in receptor terminals of both myelinated and unmyelinated fibers. In voltage-clamp studies, cell permeant cAMP analogs shifted the activation curve for I H to depolarized potentials in C-type neurons but not A-type neurons. In current-clamp recording, CsCl, which inhibits only I H in nodose neurons, hyperpolarized the resting membrane potential from Ϫ63 Ϯ 1 to Ϫ73 Ϯ 2 mV and nearly doubled the input resistance from 1.3 to 2.2 G⍀. In addition, action potentials were initiated at lower depolarizing current injections in the presence of CsCl. At the sensory receptor terminal, CsCl decreased the threshold pressure for initiation of mechanoreceptor discharge. Therefore, elimination of the I H increases excitability of both the soma and the peripheral sensory terminals.

Ion channels in mammalian vestibular afferents may set regularity of firing

“…Like many neurons, including DRG neurons (Doan et al, 2004), mouse vestibular ganglion somata have I h , the hyperpolarizationactivated mixed-cation current carried by HCN channels (Chabbert et al, 2001b), as illustrated in Fig. 3C,D.…”

“…I h is held to be involved in pacemaking -the endogenous generation of regular spikes -in cardiac cells and other neurons, although how it plays this role is THE JOURNAL OF EXPERIMENTAL BIOLOGY not understood (reviewed in Siu et al, 2006). In some settings, I h may inhibit repeated firing, as shown by blocking it in large DRG neurons (Doan et al, 2004). But blocking I h in immature mouse vestibular ganglion somata had no effect on either the spike waveform, including the AHP, or the resting potential (Chabbert et al, 2001b).…”

Hyperpolarization-activated current (Ih) contributes to excitability of primary sensory neurons in rats

“…Accordingly, I h has been shown to support spontaneous burst firing in most brain sites (Chan et al, 2004;Ghamari-Langroudi and Bourque, 2000;Lupica et al, 2001;Maccaferri and McBain, 1996;Tanaka et al, 2003), although not all (Mercuri et al, 1995). In contrast to this excitatory influence, ionic conductance through I h channels reduces the input resistance of neurons and thereby limits AP initiation in response to a depolarizing current (Doan et al, 2004;Gasparini and DiFrancesco, 1997;Maccaferri and McBain, 1996). Since I h is expressed in axons (Birch et al, 1991;Takigawa et al, 1998), reduced input resistance may increase conductance failure through points of impedance mismatch, such as the T-branch where the central and peripheral limbs of the sensory neuron axon meet with the axonal stem that leads to the neuronal soma (Luscher et al, 1994;Stoney, 1985).…”

Functional Arterial Baroreflex Attenuates the Effects of Antihypertensive Drugs in Conscious Rats

“…Although hydrochlorothiazide did not significantly decrease blood pressure, the change in PI may be induced by a reflex tachycardia secondary to the small drop of blood pressure. Another possibility might be that hydrochlorothiazide directly deactivated the baroreceptors located in the carotid sinus and aorta by altering the movement of ions (19,20), and this speculation remains to be confirmed by further SBP, systolic blood pressure; DBP, diastolic blood pressure; PI, pulse interval; before, before drug administration; after, after drug administration; Sham, sham-operated rats. n = 8 in each group.…”